Graduate Faculty - Molecular Pharmacology and Therapeutics (MPaT)

Bio

Dr. Alejandro received her Ph.D. in Physiology from the University of British Columbia.

Research Summary

Diabetes and metabolism roles of O-linked GlcNAc Transferase (OGT) signaling in pancreatic beta-cell development and programming of beta-cell susceptibility to diabetogenic conditions.

Bio

Dr. Baehr is an Assistant Professor in the Department of Pharmacology. She received her B.S. with a double major in Chemistry and Biochemistry and Molecular Biology from Rose-Hulman Institute of Technology (Terre Haute, IN) in 2011. Her graduate work in Molecular Pharmacology and Experimental Therapeutics at the Mayo Graduate School of Biomedical Sciences (Rochester, MN) explored regulation of DNA damage repair in response to antimetabolites in cancer chemotherapy. Her post-doctoral work supported by the PharmacoNeuroImmunology program at UMN focused on vaccines and monoclonal antibodies against opioids in the laboratory of Dr. Marco Pravetoni. Currently, she works with Drs. Pravetoni and Michael Raleigh to advance murine and humanized anti-fentanyl monoclonal antibodies, and related projects to isolate antibodies against other drugs of abuse and toxic compounds.

Research Summary

Vaccines and monoclonal antibodies (mAbs) targeting small molecule drugs of abuse work by sequestering the target compounds in the bloodstream, preventing diffusion across the blood-brain barrier. Such mAbs against fentanyl are able to both prevent and reverse the effects of fentanyl in animal models, and enhance the efficacy of the opioid antagonist naloxone by reducing competition with fentanyl at opioid receptors. Highly specific mAbs can also be utilized for rapid detection of their target molecule in unknown samples. Our research focuses on elucidating the pharmacology of anti-fentanyl mAbs for reversal of fentanyl overdose, and on isolation of novel mAbs against other compounds of clinical interest.

Research Summary

My laboratory is primarily interested in metabolic physiology, stress physiology and social determinants of health and aging. We developed a unique integrative approach to investigate the molecular physiology of obesity and chronic stress-related disease which combines behavioral and genetic models, metabolic, neuroendocrine and imaging techniques in living animals as well as sophisticated molecular and structural biology analyses of neuropeptides.
The major research topics include: 1) the functional role of Vgf-derived peptides in obesity and metabolism and their development as innovative drug targets for obesity-related disease; 2) autonomic nervous system regulation of white and brown adipocyte functions in obesity; 3) stress-induced cardiovascular and metabolic diseases; 4) social determinants of health, disease and aging.
Funding sources include: NIDDK, NIA, NHLBI and several Foundations

Bio

Dr. Bazzaro is a Tenured Associate Professor in the Department of Department of Obstetrics, Gynecology and Women's Health and Masonic Cancer Center at the University of Minnesota. She earned a Ph.D. in Medicinal Chemistry from the Department of Pharmaceutical Science of the University of Ferrara, Italy.

Dr. Bazzaro served as guest researcher at the "Institut de Biochemie" in Lausanne, Switzerland and at the Karolinska Institute in Stockholm, Sweden.

She competed her postdoctoral training at the Department of Pathology of the Johns Hopkins Hospital.Dr. Bazzaro is an Italian citizen, U.S.A permanent resident and speaks English, French, Spanish, and Italian.

Administrator Information

Kristina Cecka
Administrative Phone: 612-626-3111
Administrative Email: ceck0012@umn.edu

Research Summary

Dr. Bazzaro has a lifelong research interest in cervical and ovarian cancer. She combines her expertise in both the biology of ovarian cancer and pharmaceutical chemistry for the discovery of personalized medicine for women affected by cervical and ovarian cancer for which conventional chemotherapy is not a satisfactory option.

Dr. Bazzaro's has ongoing research collaboration with several institutions and hospitals, nationally and internationally.

This includes:
Mayo Clinic in Rochester, MN
Johns Hopkins Hospital in Baltimore, MD
University of Alabama in Birmingham, AL
University of Ferrara, Italy
University of Linkoping, Sweden

Research projects:
Microtubule dynamics in the context of cancer and neurodegeneration
Personalized therapies for ovarian cancer resistant to conventional chemotherapy treatment
Combinatorial chemotherapic treatment for ovarian cancer
Targeting of metabolic pathways for ovarian and cancer treatment
Role of Natural Killer (NK) cell in ovarian cancer

Study of the mechanisms underlying breast and ovarian cancer development and progression
Dr. Bazzaro's laboratory is interested in studying abnormalities of protein degradation pathways in breast and ovarian cancer. The Ubiquitin-Proteasome-System (UPS) is responsible for degradation of over 90% of short-lived intracellular proteins. Protein degradation through Ubiquitin-Proteasome-System is a multistep process that begins with de-ubiquitination of ubiquitin-tagged target molecules by de-ubiquitinating enzymes following their entrance in the 20S catalytic chamber of the proteasomes were the actual degradation occurs. The polypeptide targets of the proteasome include proteins involved in cell cycle progression, survival and inflammation and while the ubiquitin-dependent proteasomal degradation is crucial for both normal and malignant cells the higher demand for metabolic/catabolic activity associated with the malignant phenotype renders the ubiquitin-proteasome pathway a suitable tool for cancer treatment. The laboratory is particularly interested in studying the role played by proteasomal- and lysosomal-assisted protein degradation pathways during the development and the progression of breast and ovarian cancer and in the development of new small-molecules inhibitors of ubiquitin-proteasome-system for targeting breast and ovarian cancer cells.

Bio

Administrator Info

Name: Becca Johnson
Phone: 612-624-9996
Email: joh07913@umn.edu
Fax: 612-625-4410
Mail: 2101 6th Street SE, MC 2641 Room 2-118, WMBB Building, Minneapolis, MN 55455

Summary
Dr. Bold is a physician-scientist, trained in the clinical subspecialty practice of infectious diseases, and laboratory based investigations of microbiology and immunology. His clinical interests regard the care of immune-compromised patients being treated for cancer or undergoing transplantation. His lab in the Center for Immunology is focused on advancing understanding of how the adaptive immune system combats infection with Mycobacterium tuberculosis, the bacterial pathogen responsible for human TB.

Research Summary

Dr. Bold is a physician-scientist, trained in the clinical practice of infectious diseases and laboratory based investigations of microbiology and immunology. His clinical interests regard the care of immune-compromised patients being treated for cancer or undergoing transplantation. His lab in the Center for Immunology is focused on advancing understanding of how the immune system combats infection with Mycobacterium tuberculosis, the bacterial pathogen responsible for human TB, and SARS-CoV-2, the virus that causes COVID-19.

Clinical Summary

Transplant Infectious Diseases

Research Summary

Frank obtained his Ph.D. at the University of North Carolina at Chapel Hill with Dr. Clyde Hutchison III, where Frank's invention of oligonucleotide-directed DNA synthesis & cloning techniques and his discovery of the mammalian LINES-1 (L1) repetitive DNA was cited in Dr. Hutchison's admission to the National Academy of Sciences.Frank's postdoctoral work was with Drs. Greg Sutcliffe and Floyd Bloom at The Scripps Research Institute (TSRI) in La Jolla, California, where he invented "physiological engineering" with a cyclic AMP-elevating transgene and was co-designer of a genome-expression fingerprinting technique that led to the founding of Digital Gene Technologies, Inc., and Neurome, Inc., of San Diego.Frank's faculty research in the Department of Pharmacology included the invention of "brain circuit-testing" and the first transgenic mouse model of Obsessive Compulsive Disorder (OCD), Tourette's Syndrome (TS), and trichotillomania (TTM) -- from which Dr. Burton's model of hyperglutamatergic corticostriatal circuitry in such disorders has stimulated the clinical validation of antiglutamatergic drugs for OCD and TTM.Dr. Burton currently is a biotech, small pharma, & medtech inventor & entrepreneur who continues lecturing in our Department, maintains parallel academic affiliations with the Graduate Program in Neuroscience, The Masonic Cancer Center, and the Minnesota Supercomputer Institute, and retains a small University lab at the Minneapolis Medical Research Foundation (MMRF) in downtown Minneapolis' Hennepin County Medical Center (HCMC) to extend his academic research on: tic & compulsion circuitry & drug development cancer "bottleneck" genes supercomputer-aided design of abiogenic nucleic acids

Research Summary

Age is associated with increased inflammation, visceral adiposity and metabolic disease. Tissue resident immune cells are required for dampening inflammation and maintaining tissue homeostasis. There are changes in resident immune cells that drive the increased inflammation and metabolic impairments that are seen with increased age. We are studying the cellular and molecular changes within tissue resident immune cells that drive metabolic impairments in tissues. In particular, we are focused on lipolysis, a metabolic process that is required for release of energetic substrates from stored triglycerides in adipocytes. Lipolysis is impaired in aged individuals and this impairment may contributes to a worsened ability of elderly to maintain a healthy body-weight, stay warm or exercise. Our work has previously shown that adipose tissue immune cells reside in microenvironment niches and are able to inhibit lipolysis in the aged adipose tissue. There are two broad projects within the lab: Adipose tissue macrophage-specific regulatory effects on lipolysis and inflammation during aging Fat-associated lymphoid cluster (FALC) and lymphocyte regulation of metabolism Our lab focuses on mouse models of aging and uses a wide variety of techniques to investigate the changes occurring with age. We combine this in vivo approach with a complementary in vitro cell culture system to better understand a direct mechanism. Ultimately, our goal is to generate candidates that could be targets for therapeutically treating to improve health span and restore metabolism in the elderly.

Bio

Dr. Campbell emigrated to the US with his parents as a young lad and received his primary and secondary education in Connecticut. He received his B.S. degree in Biology from Fairfield University, and after a brief stint as a research technician at Yale University, matriculated in the Biochemistry PhD program at Boston University. After graduation he pursued postdoctoral training in human molecular genetics with Dr. Raju Kucherlapati, initially at the University of Illinois at Chicago, and subsequently at the Albert Einstein College of Medicine in Bronx, New York.

Research Summary

The Campbell lab is interested in how mammalian cells recognize and respond to xenobiotic-induced DNA damage. In particular, we're interested in DNA damage induced by anti-cancer agents. It is known that cells recognize this damage and respond by activating signal transduction pathways that dictate cellular responses such as: DNA repair, cell cycle arrest, and/or activation of programmed cell death. The consequences of this cellular decision-making can mean literally life or death. Mutations in key genes regulating this process can alter this DNA damage response in ways that render cancer cells unresponsive to the cytotoxic effects of anti-cancer drugs, resulting in drug resistance and patient death. On the other hand, many anti-cancer drugs evoke catastrophic levels of cell killing within normal cell populations, including stem cells within the bone marrow, gastrointestinal tract, reproductive tissues, etc. Developing a greater understanding of this highly regulated and complex cellular response has the potential to significantly impact the field of cancer chemotherapy. This insight can be utilized to develop novel therapeutics that target tumor-specific mutations in ways that enhance chemotherapeutic efficacy. In addition, it is conceivable that chemotherapy-induced death of normal cells can be mitigated in ways that reduce acute morbidity and mortality associated with aggressive anti-cancer therapies.While our lab is primarily focused on the response to DNA damage induced within chromosomes in the cell nucleus, we are also actively investigating how cells respond to damage to the mitochondrial genome. As above, the long-term objective of these studies is to gain insight that can be used to improve the safety and efficacy of cancer chemotherapy.

Research Summary

Circadian (~24 h) rhythmicity is a fundamental property of nearly all living beings on this planet. In mammals, the master pace maker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN relays photic information from the retina to the brain to synchronize endogenous rhythms to ambient light/dark cycles. Desynchronization of the endogenous rhythms can lead to fatigue, insomnia and memory loss as seen in jet lag.

Circadian clocks also exist in a variety of extra-SCN regions throughout the brain. The rhythms in these regions modulate brain activities on a daily basis. A variety of neurophysiological processes are rhythmically regulated by the circadian clock, which accounts for the time-of-day variations in our sensory, motor, memory and social functions. Conversely, disruption of circadian rhythms has been reported in patients with neurological disorders such as Alzheimer's disease and Parkinson's disease.

My lab is interested in molecular signaling mechanisms that orchestrate daily rhythms in our brain and how their dysregulation contributes to various neurological and psychiatric diseases. We are particularly interested in the role of mammalian target of rapamycin (mTOR) signaling and mechanisms that control mRNA translation in the circadian clock.Our lab utilizes a combination of molecular, cellular and behavioral technologies, including polysome profiling, RNA sequencing, qRT-PCR, Western blotting, immunocytochemistry, electrophysiology, confocal microscopy, viral-mediated gene silencing and animal behavioral analysis (e.g., circadian, social and memory tests, EEG). A variety of model systems, including cell culture, organotypic slice culture, and whole animals (transgenic and knockout mice) are employed.

We constantly look for talented and motivated undergraduate, graduate students and postdoctoral researchers to join our lab.

Research Methods/Techniques

Our lab utilizes a combination of molecular, cellular and behavioral technologies, including polysome profiling, RNA sequencing, qRT-PCR, Western blotting, immunocytochemistry, electrophysiology, confocal microscopy, viral-mediated gene silencing and animal behavioral analysis (e.g., circadian, social and memory tests, EEG). A variety of model systems, including cell culture, organotypic slice culture, and whole animals (transgenic and knockout mice) are employed.

Professional Associations

• Graduate Faculty, Graduate Program in Pharmacology
• Faculty, Graduate Program in Neuroscience
• Faculty, Integrated Biosciences Graduate Program
• Researcher, Masonic Cancer Center

Teaching Summary

Neurological Medicine
Foundation of Medicine
Mentoring/Advising: undergraduate, graduate and post-doctoral fellows.
 

Research Summary

Research Summary

Dr. Connell and colleagues are currently engaged in research into the mechanism of mammalian iron homeostasis during health and disease. The redox potential and coordination chemistry of iron in aqueous solution is exploited within a wide cross-section of biochemistry, including respiration, the synthesis of deoxyribonucleotides and the transport of oxygen. However, some of the same properties of aqueous iron that make it so valuable can also result in the generation of free radicals that are toxic to the cell. As a result, mechanisms have evolved to precisely regulate both the organismal and intracellular iron concentration. Understanding these mechanisms is highly relevant to the development of novel drugs for the treatment of a wide range of pathologies in which iron homeostasis has been perturbed, including cancer. The transferrin receptor (TfR1) is the primary means of iron importation for most mammalian cells, and the regulation of mRNA stability in response to changing intracellular iron is a major mechanism through which TfR1 expression is controlled. The focus of the lab has been to identify the process through which the stability of the TfR1 mRNA is regulated in response to changing intracellular iron. The approach taken initially involved defining the features within the 3' UTR of the TfR1 mRNA that are essential for iron-responsive degradation, which include three highly conserved hairpin loops (Figure 1). These have subsequently been exploited as probes to identify the key protein mediating the iron-responsive degradation. Current studies are focused upon characterizing the mechanism involved with the process as well as exploring its potential as a therapeutic target for the treatment of pathologies related to disorders of iron regulation. Figure 1. Three short hairpin loops (red) within the 3' UTR of the TfR1 mRNA were defined as essential for iron-responsive degradation (Dhwani & Connell, RNA vol 22 (8) 1271-82, 2016). The lab has recently exploited these features to identify the protein that mediates the degradation.

Bio

Administrative Contact: Kelli Tourand |  612-624-4581 | toura018@umn.edu

Dr. Davydova is an Associate Professor at the Department of Surgery at the University of Minnesota (UMN). She is also a faculty member at the UMN Institute for Molecular Virology, Masonic Cancer Center, Center for Genome Engineering, and MD/PhD Medical Scientist Training Program. 

Dr. Davydova has over 20 years of experience in the field of gene therapy and cancer research. As a member of the Gene Therapy Center at the University of Alabama at Birmingham (UAB), she was directly involved in the development of first generations of adenoviral vectors for malignant diseases and establishment of standardized procedures for virus manufacturing. Her scientific contribution has resulted in developing critical elements to improve infectivity and specificity of adenovirus-based vectors which extended their utility for human gene therapy. 

Since joining the Department of Surgery and the Masonic Cancer Center at the UMN in 2006, Dr. Davydova’s research is focused on the clinical translation of adenovirus-based technologies for cancer patients. Her work with a focus on oncolytic adenovirus-mediated therapies for pancreatic cancer was funded by multiple awards including two NIH R01 grants.  

Dr. Davydova is a member of several professional societies, including American Society of Gene and Cell Therapy, American Association of Cancer Research, American Pancreatic Association and serves as an Academic and/or Guest editor in professional journals. She is also actively participating as a reviewer at multiple NIH study sections (e.g., Translational Immuno-Oncology (TIO), Radiation Therapeutics and Biology (RTB), Clinical and Translational Exploratory/Developmental Studies) and many international grant review panels. 

Dr. Davydova is a productive mentor to numerous laboratory trainees at different levels including undergrad and graduate students, medical scholars, postdoctoral fellows, surgical residents, and junior faculty.

Education

Dr. Davydova received her M.D. and Ph.D. in Pathophysiology and Molecular Biology from the Siberian State Medical University in Tomsk, Russia. In 2000, she was invited to join the Gene Therapy Center at the University of Alabama at Birmingham (UAB), where she obtained extensive training in virus-based gene therapy and cancer research.

Research Summary

Dr. Davydova’s current goals are focused on the clinical translation of oncolytic adenovirus for cancer patients, including patients with pancreatic, breast, melanoma, and sarcoma malignances. 

Her research focus includes but is not limited to:

• Development of oncolytic adenovirus as a platform for cancer therapy and imaging. 
• Development of novel virus-based immunotherapies for cancer patients.
• Clinical translation of oncolytic adenovirus from “bench to bed”. 
• Development of immunocompetent preclinical models for oncolytic virus therapy and cancer research. 

Selected Publications

• Osipov, I. D., Vaskihovskaia, V. A., Zabelina, D. S., Kutseikin, S. S., Grazhdantseva, A. A., Kochneva, G. V., Davydova, J., Netesov, S. V., Romanenko, M. V. (2023). Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment. Viruses 2023, 15 (1), 182.  doi: 10.3390/v1510182
• Romanenko, M., Osipov, I., Netesov, S. V., Davydova, J. (2021). Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy. Pharmaceutics, 13(10). PMID: 34683934 PMCID: PMC8540711 doi: 10.3390/pharmaceutics13101641
• Robertson, M. G., Eidenschink, B. B., Iguchi, E., Zakharkin, S. O., LaRocca, C. J., Tolosa, E. J., Truty, M. J., Jacobsen, K., Fernandez-Zapico E., Davydova, J. (2021). Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion. Mol Ther Oncolytics(5;20), 659-668. PMID: 33816784 PMCID: PMC7985464 doi: 10.1016/j.omto.2021.03.002
• Koodie, L., Robertson, M. G., Chandrashekar, M., Ruth, G., Dunning, M., Bianco, R. W., Davydova, J. (2019). Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses. Cancers, 11(2). PMID: 30744019 PMCID: PMC6406826 doi: 10.3390/cancers11020198
• Shapovalova, M., Davydova, J., Henzler, C., Daniel, M., Dehm, S. M., Warlick, C. A., LeBeau, A. M. (2018). Exploiting the transcriptional specificity of the alpha-methylacyl-CoA racemase AMACR promoter for the molecular imaging of prostate cancer. Oncotarget, 9(94), 36693-36704. PMID: 30613352 PMCID: PMC6291171 doi: 10.18632/oncotarget.26401
• Salzwedel, A. O., Han, J., LaRocca, C. J., Shanley, R., Yamamoto, M., Davydova, J. (2018). Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer. Oncotarget, 9(26), 18041-18052. PMID: 29719589 PMCID: PMC5915056 doi: 10.18632/oncotarget.24710
• LaRocca, C. J., Davydova, J. (2016). Oncolytic Virotherapy Increases the Detection of Microscopic Metastatic Disease at Time of Staging Laparoscopy for Pancreatic Adenocarcinoma. EBioMedicine, 7, 15-6. PMID: 27322450 PMCID: PMC4909609 doi: 10.1016/j.ebiom.2016.05.019
• Tasca, A., Stemig, M., Broege, A., Huang, B., Davydova, J., Zwijsen, A., Umans, L., Jensen, E. D., Gopalakrishnan, R., Mansky, K. C. (2015). Smad1/5 and Smad4 expression are important for osteoclast differentiation. Journal of cellular biochemistry, 116(7), 1350-60. PMID: 25711193 PMCID: PMC4431909 doi: 10.1002/jcb.25092
• LaRocca, C. J., Han, J., Gavrikova, T., Armstrong, L., Oliveira, A. R., Shanley, R., Vickers, S. M., Yamamoto, M., Davydova, J. (2015). Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer. Surgery, 157(5), 888-98. PMID: 25731784 PMCID: PMC4417428 doi: 10.1016/j.surg.2015.01.006
• Davydova, J., Yamamoto, M. (2013). Oncolytic adenoviruses: design, generation, and experimental procedures. Current protocols in human genetics, Chapter 12, Unit 12.14. PMID: 23853080  doi: 10.1002/0471142905.hg1214s78
• Mansky, K. C., Jensen, E. D., Davydova, J., Yamamoto, M., Gopalakrishnan, R. (2013). Protein Kinase D Promotes In Vitro Osteoclast Differentiation and Fusion. J Biol Chem, 288(14), 9826-9834.  
• Oneal, M. J., Trujillo, M. A., Davydova, J., McDonough, S., Yamamoto, M., Morris, 3rd, J. C. (2013). Effect of increased viral replication and infectivity enhancement on radioiodide uptake and oncolytic activity of adenovirus vectors expressing the sodium iodide symporter. Cancer gene therapy, 20(3), 195-200. PMID: 23412431  doi: 10.1038/cgt.2013.4
• Miura, Y., Yamasaki, S., Davydova, J., Brown, E., Aoki, K., Vickers, S., Yamamoto, M. (2013). Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library. Molecular therapy : the journal of the American Society of Gene Therapy, 21(1), 139-48. PMID: 23032977 PMCID: PMC3538312 doi: 10.1038/mt.2012.205
• Armstrong, L., Arrington, A., Han, J., Gavrikova, T., Brown, E., Yamamoto, M., Vickers, S. M., Davydova, J. (2012). Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy. American journal of surgery, 204(5), 741-50. PMID: 22748294 PMCID: PMC3467355 doi: 10.1016/j.amjsurg.2012.02.016
• Oneal, M. J., Trujillo, M. A., Davydova, J., McDonough, S., Yamamoto, M., Morris, 3rd, J. C. (2012). Characterization of infectivity-enhanced conditionally replicating adenovectors for prostate cancer radiovirotherapy. Human gene therapy, 23(9), 951-9. PMID: 22694073 PMCID: PMC3440023 doi: 10.1089/hum.2012.047
• Pham, L., Beyer, K., Jensen, E. D., Rodriguez, J. S., Davydova, J., Yamamoto, M., Petryk, A., Gopalakrishnan, R., Mansky, K. C. (2011). Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. Journal of cellular biochemistry, 112(3), 793-803. PMID: 21328453 PMCID: PMC3335346 doi: 10.1002/jcb.23003
• Davydova, J., Gavrikova, T., Brown, E. J., Luo, X., Curiel, D. T., Vickers, S. M., Yamamoto, M. (2010). In vivo bioimaging tracks conditionally replicative adenoviral replication and provides an early indication of viral antitumor efficacy. Cancer science, 101(2), 474-81. PMID: 19900190 PMCID: PMC4584507 doi: 10.1111/j.1349-7006.2009.01407.x
• Ramírez, P. J., Vickers, S. M., Ono, H. A., Davydova, J., Takayama, K., Thompson, T. C., Curiel, D. T., Bland, K. I., Yamamoto, M. (2008). Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model. American journal of surgery, 195(4), 481-90. PMID: 18361926  doi: 10.1016/j.amjsurg.2007.04.014
• Le, L. P., Le, H. N., Dmitriev, I. P., Davydova, J. G., Gavrikova, T., Yamamoto, S., Curiel, D. T., Yamamoto, M. (2006). Dynamic monitoring of oncolytic adenovirus in vivo by genetic capsid labeling. Journal of the National Cancer Institute, 98(3), 203-14. PMID: 16449680  doi: 10.1093/jnci/djj022
• Davydova, J., Le, L. P., Gavrikova, T., Wang, M., Krasnykh, V., Yamamoto, M. (2004). Infectivity-enhanced cyclooxygenase-2-based conditionally replicative adenoviruses for esophageal adenocarcinoma treatment. Cancer research, 64(12), 4319-27. PMID: 15205347  doi: 10.1158/0008-5472.CAN-04-0064
• Le, L. P., Everts, M., Dmitriev, I. P., Davydova, J. G., Yamamoto, M., Curiel, D. T. (2004). Fluorescently labeled adenovirus with pIX-EGFP for vector detection. Molecular imaging, 3(2), 105-16. PMID: 15296675  doi: 10.1162/1535350041464874
• Yamamoto, M., Davydova, J., Wang, M., Siegal, G. P., Krasnykh, V., Vickers, S. M., Curiel, D. T. (2003). Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer. Gastroenterology, 125(4), 1203-1218.  doi: 10.1016/S0016-5085(03)01196-X

Research Summary

Dr. Dehm is a member of the Division of Molecular Pathology and Genomics.  His research laboratory focuses on the role of the androgen receptor (AR) and alterations in AR signaling in prostate cancer development and progression. As they develop, nearly all metastatic prostate cancers remain dependent on androgens--male hormones of which testosterone is best known. Following treatment targeting the AR including anti-androgen drug therapies and surgical castration to prevent androgen production, patients typically develop resistance. Dehm studies the changes that occur in the AR in response to these drug therapies to understand the mechanisms underlying the progression to therapy-resistant disease. His work has revealed new ways in which cancer cells can re-activate the androgen/AR pathway. If these mechanisms are better understood, new AR-targeted therapies could be developed that suppress prostate cancer growth more effectively with more durable remissions.Dr. Dehm's research team employs a variety of genomic engineering, molecular biology, and biochemistry tools to home in on the regulatory behavior of the AR and the signals it uses to promote resistance. These tools are used to analyze clinical tissues, prostate cancer cell lines, models in which patient-derived tumor tissue is grown in mice (xenografts), and fresh surgical tissue that is propagated in the laboratory as explants. Dehm and his colleagues have found that altered protein forms of the AR, termed AR variants, can be synthesized in resistant tumors. These AR variants are missing the site of the protein responsible for binding to androgens, which is the same site to which anti-androgens bind. However, these AR variants retain all other parts of the protein that are required for binding to DNA and activation of transcription. Therefore, these AR variants are able to carry out most of the functions of the AR protein, but in a way that no longer require androgens and is completely insensitive to anti-androgens. Dehm and his co-investigators are now focused on understanding how these AR variants are regulated, with the ultimate goal of finding ways to inhibit them.Transcription factors like AR variants are challenging drug targets because key binding events occur via protein:DNA or protein:protein interfaces rather than through the lock-and-key mechanism of androgen binding to the AR, which medicinal chemists can more readily exploit. However, Dehm notes that recent advances in small-molecule design and peptide chemistry have overcome some of these challenges, and could potentially be applied to AR variants. Ultimately, identifying and targeting key processes required for AR variants to remain active in prostate cancer cells could provide an avenue to overcome the challenge of therapeutic resistance in patients.

Publications

Daniel M, Knutson TP, Sperger JM, Li Y, Singh A, Stahlfeld CN, Passow C, Auch B, Lang JM, Dehm SM. AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer. Endocr Relat Cancer. 2021 Aug 11;28(9):645-655. doi: 10.1530/ERC-21-0157.

Li Y, Yang, R, Henzler C, Ho Y, Passow C, Auch B, Carreira S, Rodrigues DN, Bertan C, Hwang TH, Quigley DA, Dang HX, Morrissey C, Fraser M, Plymate SR, Maher CA, Feng FY, De Bono J, Dehm SM. Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer. Clin. Cancer Res., 26(8):1965-1976, 2020.

Yang R, Van Etten JL, and Dehm SM. Indel detection from DNA and RNA sequencing data with transIndel. BMC Genomics, 2018; 19(1):270. doi: 10.1186/s12864-018-4671-4..

Zadra G, Ribeiro CF, Chetta P, Ho Y, Cacciatore S, Gao X, Syamala S, Bango C, Photopoulos C, Huang Y, Tyekucheva S, Bastos DC, Tchaicha J, Lawney B, Uo T, D'Anello L, Csibi A, Kalekar R, Larimer B, Ellis L, Butler LM, Morrissey C, McGovern K, Palombella VJ, Kutok JL, Mahmood U, Bosari S, Adams J, Peluso S, Dehm SM, Plymate SR, Loda M. Inhibition of de-novo lipogenesis targets androgen receptor signaling in castration resistant prostate cancer. Proc. Natl. Acad. Sci. USA. 116: 631-640, 2019.

Bio

Dr. Drake is a Prostate Cancer Foundation Young Investigator and a Masonic Scholar. He received his B.S. degree from Minnesota State University, Mankato in Biochemistry and Ph.D. degree from the University of Iowa in the Department of Molecular Physiology and Biophysics in the laboratory of Dr. Michael D. Henry. His postdoctoral training was in the lab of Dr. Owen N. Witte at UCLA. Prior to coming to the University of Minnesota in 2018, Dr. Drake held a faculty position at the Rutgers Cancer Institute of New Jersey in the Department of Medicine.

Research Summary

Research in the Drake Lab focuses on blending basic and translational research approaches to better understand the signaling networks in lethal metastatic castration resistant prostate cancer, and how to more effectively treat patients who are suffering from this disease using rationalized targeted therapies. Previous research from Dr. Drake and others suggest that kinase activation may be a primary mechanism of resistance to current therapies in late stage prostate cancer. Using in vivo primary mouse and human cancer model systems, the Drake Lab investigates what particular kinase signaling pathways are activated that lead to this resistance and how new targeted therapies, such as kinase inhibitors, may perturb these pathways for future clinical utility.In addition, Dr. Drake's lab will also employ phosphoproteomics enrichment technologies coupled to quantitative targeted mass spectrometry to identify the activated kinases and pathways in pre-clinical and clinical tumors for development of predictive biomarkers. The results of this research aim to evaluate single liquid or tissue biopsies from metastatic prostate cancer patients for activated kinase signatures that will lead to targeted therapies in real time.

Bio

Dr. Driscoll attended Harvey Mudd College, where she received a B.S. in Physics. She then earned a Ph.D. in Physics from the University of Maryland, working under the mentorship of Dr. Wolfgang Losert. Moving to the University of Texas Southwestern Medical Center, she joined the lab of Dr. Gaudenz Danuser as a Postdoctoral Fellow and later Instructor. Dr. Driscoll became an Assistant Professor in the Department of Pharmacology in 2022.

Research Summary

Cells have convoluted and dynamic morphologies. Their morphology is a critical element of the vast signaling network regulating cellular functioning. Focusing on cancer and immune cells, which are often highly dynamic, the Driscoll lab investigates how the interplay between cell morphology, dynamics, and signaling governs cell function. To visualize quick subcellular dynamics, we use state-of-the-art microscopy, especially high-resolution light-sheet microscopy. The detailed 3D movies produced by these microscopes necessitate dedicated computational pipelines, and so we develop algorithms rooted in computer graphics, computer vision and machine learning to facilitate biological discovery.
 

Bio

Dr. Freedman is an Assistant Professor of Pharmacology, housed in the Center for Immunology at University of Minnesota (UMN). She is also a member of the UMN Masonic Cancer Center's Immunology Program and the Center for Autoimmune Diseases Research. She received her AB degree with honors in Biochemistry from Bowdoin College (Brunswick, ME) before moving to UC Berkeley to enter the PhD program in Molecular and Cell Biology. Working jointly in the laboratories of Drs. John Kuriyan and Susan Marqusee, Dr. Freedman discovered structural and dynamic mechanisms underlying differential allosteric activation of the Ras-activating proteins Sos and RasGRF1. As a postdoc with Dr. Arthur Weiss at UCSF, she discovered a mechanism by which the Src-family kinase LynA tunes macrophage sensitivity to pro-inflammatory activation, a process with implications for myeloid-cell hypersensitization in autoimmune disease. Dr. Freedman's independent research program at UMN focuses on how myeloid cells integrate positive- and negative-regulatory signals to achieve tissue-specific functions and drive pathologies from autoimmune diseases to breast cancer. Protein tyrosine kinases, including Lyn and the other Src-family kinases, are modulators of cell sensitivity, and thus cell- and receptor-specific modes of kinase regulation and function are areas of special interest to her lab.

Research Summary

Immune cells are tuned exquisitely to identify pathogens and avoid hypersensitivity. In macrophages Src-family tyrosine kinases (LynA, LynB, Hck, and Fgr) regulate a size sensing mechanism based on their ability to nucleate clustering of ITAM-coupled receptors. Under normal circumstances small debris cannot trigger macrophage activation, but this regulatory process can be subverted in inflamed tissues. We are studying how the Src-family kinases, especially LynA, tune the sensitivity of macrophages and other immune cells to triggering and the regulation or dysregulation of these processes in autoimmune disease, infection, and breast cancer.

Research Summary

The principal aim of my laboratory is to understand the molecular pathways that drive neuronal death in Huntington´s Disease (HD), an inherited neurodegenerative disorder caused by a CAG triplet repeat expansion within exon-1 of the Huntingtin gene (Htt). Mutant Htt protein aggregates and accumulates in virtually all cell types in the body, but it predominantly affects Medium Spiny Neurons (MSNs), a neuronal type located in the striatum. We focus on studies directed at understanding what makes MSNs so susceptible to mHtt aggregation and death compared to other cell types in the brain. We also examine the role of Heat Shock Factor (HSF1), a transcription factor that regulates protein folding, inflammation, and apoptosis, in a cell type-specific process. To address this question we apply molecular biology, biochemistry, neuroanatomy, and imaging to different HD cellular and mouse models as well as human specimens. Our final goal is to provide new therapeutic strategies to prevent neuronal death and improve the quality of life of thousands of patients with this devastating neurodegenerative disease.

Bio

Our lab is interested in how cell surface receptors convert signals from extracellular stimuli like mechanical force into a biological response.

Research Summary

Our lab is interested in how cell surface receptors convert signals from extracellular stimuli like mechanical force into a biological response, as dysregulation in a cell's force-sensing ability can lead to disease. We use X-ray crystallography and other biophysical methods to ask what "mechanosensors" look like in order to understand the range of structures nature uses to sense forces of different magnitudes and in different contexts, and hopefully identify potentially novel therapeutic targets. We also use and develop single molecule and cell-based assays based on magnetic tweezers to apply forces to mechanosensors to probe how mechanosensors are converted from an "off" to "on" state. We measure both magnitudes of forces to effect a biological response and are developing methods to probe the corresponding structural changes that occur. Finally, we are developing general signaling assays to help us map mechanosensor domains, understand differences between on and off states, and search for new potential mechanosensors.

Bio

Dr. Graves received his B.Sc. degree from the University of Michigan in Biopsychology & Cognitive Sciences and Ph.D. degree from Rush University Medical Center in the Department of Pharmacology. His postdoctoral training was in the laboratory of Dr. D. James Surmeier at Northwestern University in the Department of Physiology. Prior to joining the University of Minnesota in 2018, Dr. Graves was a research assistant professor at Northwestern University in the Department of Physiology.

Research Summary

My lab is focused on studying functional and anatomical adaptations that arise from perturbations in dopaminergic signaling. To gain insights into this broad topic we mainly focus on two disease states; 1) Parkinson's disease where dopaminergic neurons in the substantia nigra pars compacta progressively degenerate resulting in motor dysfunction (i.e. resting tremor, postural instability, bradykinesia, etc.) and 2) drug addiction wherein a drug of abuse such as methamphetamine increases dopamine signaling and when administered repeatedly can result in drug-seeking behavior that persists long after drug-taking has ceased. By studying how the brain adapts in animal models of these diseases, we can identify what changes are pathological and play a causal role in manifesting behavioral symptoms. Once the adaptations are identified we can then move forward with to test how the adaptations influence behavioral outcomes.Projects in my lab use state-of-the-art techniques including patch clamp electrophysiology in ex vivo brain slices paired with two-photon microscopy, optogenetics, and chemogenetics. These techniques are applied to study intrinsic and synaptic dynamics in disease states that can then be translated to behaving animals. Research efforts are primarily focused on dopaminergic neurons in the substantia nigra pars compacta and spiny projection neurons in the striatum.

Research Summary

Dr. Groman's research is aimed at understanding the neurobiology and neurodevelopmental mechanisms of decision making to identify biological targets that could be manipulated to prevent and treat mental illness. She received her Ph.D. in 2013 from the Department of Psychology at the University of California, Los Angeles where she trained under Dr. J. David Jentsch and Dr. Edythe London. Her work integrated neuroimaging, behavioral, pharmacological and ex vivoapproaches to provide the first evidence that chronic exposure to methamphetamine resulted in the neural and behavioral alterations that had been previously observed in substance-dependent individuals. Her work was recognized by several awards, including a predoctoral NIH NRSA fellowship, the UCLA Brain Research Institute Award and the Joseph A. Gengerelli Distinguished Dissertation Award. She accepted a post-doctoral position in the Department of Psychiatry at Yale University where she trained under Dr. Jane Taylor in studies investigating the biobehavioral mechanisms of addiction. In 2016 Dr. Groman was promoted to Associate Research Scientists at Yale University where her work has focused on understanding the neural circuits of decision-making and addiction. She integrates computational approaches with neuroimaging, proteomics, and drug self-administration in rodents to provide a translational platform for understanding the biological and neurodevelopmental mechanisms of addiction vulnerability. The Groman Lab in the Department of Neuroscience at the University of Minnesota will be a part of the Medical Discovery Team on Addiction and focused on identifying the neural and developmental mechanisms of addiction susceptibility.

Bio

Dr. Hecht's laboratory is focused on understanding the ways tobacco smoke constituents cause cancer. To do this he and his colleagues study the mechanisms by which these compounds enter the human body, are metabolized, and ultimately bind to DNA, causing mutations that result in cancer. Cigarette smoke contains more than 70 carcinogens. Hecht focuses on several including tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons (PAH), and certain volatiles such as formaldehyde, acetaldehyde, and acrolein that are formed during the combustion process.Hecht's research team has developed methods to analyze human urine for these compounds and their metabolites. These methods, which employ mass spectrometry as a key analytic technology, enable his laboratory to take part in studies of thousands of smokers. Hecht's group also uses mass spectrometry methods to analyze the DNA damage caused by the carcinogens at the level of stereochemistry, which shows the relative spatial arrangement of atoms and molecules.The goal of Hecht's research is two-fold: First, to provide evidence in support of ongoing regulation of tobacco products due to their harm to human health, and second, to find ways to identify the susceptible smoker. That smoking causes lung cancer is well established, but it is not yet possible to identify which smokers are most likely to contract lung cancer, which would allow for early intervention. Collaboration between research groups in the fields of genetics, biochemistry, psychology and other fields will be needed to turn promising leads of an individual smoker's susceptibility to lung cancer into a preventive strategy.Hecht has a long-standing collaboration with a University colleague in psychiatry who is studying the mechanisms of addiction. Given that more than a billion people of the world's population of seven billion people are smokers, including an estimated 45 million in the U.S. and 300 million in China, the impact of learning the biological and psychological mechanisms involved in tobacco smoke addiction is a major public health challenge and opportunity. Understanding these mechanisms also can lead to the identification of smoking prevention strategies and potential chemopreventive agents.

Research Summary

Publications

PubMed Bibliography

1.Ma, B.; Stepanov, I.; Hecht, S. S. Recent studies on DNA adducts resulting from human exposure to tobacco smoke. Toxics 2019, 7.

2.Ma, B.; Villalta, P. W.; Hochalter, J. B.; Stepanov, I.; Hecht, S. S. Methyl DNA phosphate adduct formation in lung tumor tissue and adjacent normal tissue of lung cancer patients. Carcinogenesis 2019.

3.Li, Y.; Ma, B.; Cao, Q.; Balbo, S.; Zhao, L.; Upadhyaya, P.; Hecht, S. S. Mass Spectrometric quantitation of pyridyloxobutyl DNA phosphate adducts in rats chronically treated with N'-nitrosonornicotine. Chem. Res. Toxicol. 2019, 32, 773-783.

4.Stram, D. O.; Park, S. L.; Haiman, C. A.; Murphy, S. E.; Patel, Y.; Hecht, S. S.; Le Marchand, L. Racial/ethnic differences in lung cancer incidence in the multiethnic cohort study: an update. J. Natl. Cancer Inst. 2019.

5.Goniewicz, M. L.; Smith, D. M.; Edwards, K. C.; Blount, B. C.; Caldwell, K. L.; Feng, J.; Wang, L.; Christensen, C.; Ambrose, B.; Borek, N.; van Bemmel, D.; Konkel, K.; Erives, G.; Stanton, C. A.; Lambert, E.; Kimmel, H. L.; Hatsukami, D.; Hecht, S. S.; Niaura, R. S.; Travers, M.; Lawrence, C.; Hyland, A. J. Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA Netw. Open 2018, 1, e185937.

Bio

Alon Herschhorn Ph.D. is an Assistant Professor in the Department of Medicine at the University of Minnesota. Prior to his current faculty appointment, Dr. Herschhorn held a faculty position as Instructor in Microbiology and Immunobiology at Dana-Farber Cancer Institute and Harvard Medical School, where he developed strong research program on virus entry and fate, with a specific focus on HIV-1. Dr. Herschhorn successfully obtained the prestigious Rothschild and amfAR fellowships as well as external funding, and developed productive collaborations with different research groups in USA and Canada.Dr. Herschhorn is leading a new research group in the Division of Infectious Diseases and International Medicine that will develop new tools to study, at the molecular and cellular levels, the mechanisms underlying virus-host interactions. His previous work provided new insights into the entry process of HIV-1, the conformational dynamics of the HIV-1 envelope glycoproteins, and the cellular processes that contribute to the fate of viral infection.

Research Summary

My laboratory is working on exciting directions to understand and target HIV-1 host interactions at the molecular and cellular levels. We use interdisciplinary approaches at the interface of synthetic and molecular virology, immunology and cell biology to gain new insights into complex biological processes with the aim of translating these insights into novel therapies and vaccines to treat and prevent viral infections.

Clinical Summary

HIV-1 infection and latency; HIV-1 vaccine and eradication

Bio

Dr. Hiasa is an Associate Professor of Pharmacology and the Director of Undergraduate Studies (DUGS) in Pharmacology. He received his B.S. in Molecular Biology from Kyoto University and earned his M.S. in Biophysical Chemistry and Ph.D. in Molecular Biology from Kyoto University Graduate School in Kyoto, Japan. He worked as a visiting research scientist at New York University Medical Center and received postdoctoral training at Memorial Sloan-Kettering Cancer Center in New York, NY before joining the Department of Pharmacology at the University of Minnesota-Twin Cities.

Research Summary

Dr. Hiasa's laboratory studies the mechanisms of topoisomerases, as well as antibacterial and anticancer drugs that target topoisomerases. Topoisomerases are essential enzymes that catalyze DNA unlinking. As such, these enzymes play critical roles in almost every aspect of DNA metabolism, especially DNA replication and chromosome segregation. Their importance is underscored by the fact that these enzymes are the cellular targets of certain anticancer drugs in eukaryotes and, in prokaryotes, both DNA gyrase and topoisomerase IV are the targets of the most potent broad-spectrum antibacterial drugs. Dr. Hiasa and his collaborators discovered novel quinolone-based human topoisomerase I catalytic inhibitors and are currently conducting the preclinical studies of these compounds to develop them as a new class of anticancer agents. Dr. Hiasa's group is also involved in studies on various DNA gyrase and human topoisomerase II inhibitors. Mechanisms of human topoisomerase I poisons (camptothecin) and our novel human topoisomerase I catalytic inhibitors (N1-biphenyl fluoroquinolone)

Bio

My lab is primarily interested in T cell development in the thymus. We study how selection processes shape the T cell repertoire to achieve a highly effective and self-tolerant adaptive immune system.

Research Summary

Primarily interested in T cell development in the thymus. We study how selection processes shape the T cell repertoire to achieve a highly effective and self-tolerant adaptive immune system. Current research is focused on these four topics: Positive selection: This is a crucial stage in T cell development, where MHC restricted progenitors are selected from a random pool. We are systematically studying the gene changes that occur in the T cell progenitor during positive selection and how they support the multiple facets of this event (e.g. survival, migration, allelic exclusion, etc). We are also exploring how cortical epithelial cells support the process of positive selection Negative selection : One of the ways the immune system copes with self-reactive T cells is to eliminate them from the repertoire. We developed a highly physiologic in vivo mouse model to study the specific antigen-presenting cell types involved and the timing and anatomic location of negative selection. We are also exploring why some self-reactive cells undergo apoptosis, but others are selected to become regulatory T cells or NKT cells. Thymic Emigration : The lab is currently interested in the final stages of maturation that occur prior to migration of the progenitor from the thymus to the periphery. We seek to understand how the functional competence of the cell is eventually switched from apoptosis to proliferation, and the signals, molecular factors, and anatomic structures involved in emigration itself. Recent studies have focused heavily on the transcription factor KLF2. The Human T cell repertoire : We have a unique collaboration with a clinical virology group to study immune responses in humans that are at high risk for natural infection with a gamma herpesvirus (Epstein Barr Virus or EBV). In addition to documenting the precise changes that occur during the innate and adaptive immune response to this virus, we are exploring how the pre-immune T cell repertoire in such individuals is predisposed to make a pathologic response to this virus (infectious mononucleosis).

Publications

• Zhang, Z., Salgado, O. C., Liu, B., Moazzami, Z., Hogquist, K. A., Farrar, M. A. & Ruan, H. B. An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism. Frontiers in immunology; 2022, 13, 874863.

• Peng, C., Huggins, M. A., Wanhainen, K. M., Knutson, T. P., Lu, H., Georgiev, H., Mittelsteadt, K. L., Jarjour, N., Wang, H., Hogquist, K. A., Campbell, D. J., Borges da Silva, H. & Jameson, S. C., Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells.  Immunity; Jan 11 2022; 55, 1, p. 98-114.e5

• Georgiev, H., Peng, C., Huggins, M.A., Jameson S. C., Hogquist, K.A. Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells. Nat Commun 12, 2308 (2021). https://doi.org/10.1038/s41467-021-22589-z

• Ruscher R, Thera Lee S, Salgado OC, Breed ER, Osum SH, and Hogquist KA. Intestinal CD8?? IELs derived from two distinct thymic precursors have staggered ontogeny. J Exp Med 3 August 2020; 217 (8): e20192336. doi: https://doi.org/10.1084/jem.20192336

• Wang H, Breed ER, Lee YJ, Qian LJ, Jameson SC, Hogquist KA. Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22262-22268. doi: 10.1073/pnas.1910412116. Epub 2019 Oct 14.

• Borges da Silva H, Beura LK, Wang H, Hanse EA, Gore R, Scott MC, Walsh DA, Block KE, Fonseca R, Yan Y, Hippen KL, Blazar BR, Masopust D, Kelekar A, Vulchanova L, Hogquist KA, Jameson SC. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature. 2018 Jul;559(7713):264-268. doi: 10.1038/s41586-018-0282-0. Epub 2018 Jul 4. 

Bio

Dr. Kelekar's laboratory is focused primarily on altered metabolism in cancer, a fairly new field of research. The way metabolic pathways operate differently in malignant versus healthy tissue is proving to be one of the hallmarks of cancer. Kelekar initiated her work in cancer metabolism while studying the mechanisms underlying apoptosis or programmed cell death, specifically the role of bcl-2 and other protein families in regulating apoptosis. Interactions between bcl-2 proteins and the bcl-2 homology domain 3 (BH3)-only proteins are pivotal in regulating apoptosis. Dr. Kelekar's group discovered that the BH3-only protein Noxa, a canonical death-promoting protein, for example, also plays a role in cancer cell metabolism. Noxa is induced in response to apoptotic stimuli in most human cells of epithelial origin but is constitutively expressed in proliferating myeloid and lymphoid cells and required for apoptosis in response to glucose stress. Kelekar and her colleagues identified a serine on Noxa that was phosphorylated by the kinase Cdk5 in myeloid and lymphoid cancers. This amino acid modification inactivates Noxa's apoptotic or cell-killing function, potentially giving tumor cells that can employ this mechanism a survival advantage. Cells can use glucose to trigger the apoptosis avoidance mechanism such as the one enabled by Cdk5-inhibited Noxa. Kelekar and her colleagues propose that the serine residue on Noxa can serve as a glucose-sensitive "toggle switch" controlling both proliferation and apoptosis in leukemias and lymphomas. Normal cells use glucose for the energy-generating chemical reactions that take place in mitochondria through the TCA (tricarboxylic acid) cycle. Kelekar has found that Noxa expression promotes diversion of glucose for the production of biomass and that mitochondria of Noxa-overexpressing cancer cells, as well as proliferating normal cells, use the amino acid glutamine rather than glucose to supply the cell's energy needs. Interestingly, it turns out that Noxa regulates multiple metabolic functions in leukemia cells in addition to regulating glucose and glutamine utilization. Metabolomics tools can now be employed to delineate the metabolic signaling pathways that normal and cancer cells employ to carry out critical biochemical functions. Sorting out the highly sensitive metabolic needs of cancer cells and targeting key molecules like Noxa constitute a promising avenue for small-molecule drug development.

Research Summary

Mechanisms of Apoptosis Research in my laboratory focuses on pathways of cell survival and death with special emphasis on Bcl-2 family proteins as regulators of these pathways. Interactions between multi-domain Bcl-2 proteins and members of the BH3-only Bcl-2 family sub-class are pivotal in promoting cell death. Recently, our studies on human BH3-only protein, Noxa, have revealed a post-translational regulatory pathway that suppresses its pro-apoptotic function and imparts to it a novel metabolic and pro-survival role in human hematological malignancies. We are currently investigating the role of this protein and its binding partner, Mcl-1L, in regulating glucose metabolism in leukemia cells. The recognition that cancer cells exhibit altered metabolism and depend heavily on glucose as their major source of energy is leading to novel therapeutic strategies targeted at glycolytic (glucose breakdown) pathways. Major research areas in the laboratory are briefly described below:

Current Research 

Autophagy – its role in cell survival and tumor progression DNA damaging drugs induce apoptosis via the intrinsic pathway through apoptosome formation and caspase-9 activation. MCF-7 breast cancer cells show little to no caspase-9 activation and a delayed death response response to DNA damaging drugs. Further investigation identified autophagy or "self-consumption" as the underlying mechanism for the delayed apoptotic response. Our studies suggested that reduced autophagy may be an adaptive strategy in immortalized and non-invasive breast tumor cells faced with genotoxic stress and underscored the need for autophagy inhibitors in combination with conventional chemotherapeutic drugs in treating early breast cancers (Abedin et al 2007). We are currently focusing some of our research efforts on the contribution of defective autophagy to tumor initiation and progression in breast cancer. In collaboration with the group of Dr. S. Ramakrishnan at the University of Minnesota we have investigated the mechanism of action of the angiogenic inhibitor peptides, kringle 5 and endostatin, in human endothelial cells. These studies (Bui-Nguyen et al2007 and 2009) suggested that both kringle 5 and endostatin induced an apoptotic as well as an autophagic response in endothelial cells, but interfering with the autophagic survival response sensitized cells to the anti-angiogenic effects of the inhibitors by promoting a switch to robust apoptotic cell death. BH3-only protein, Noxa – its role in apoptosis and glucose metabolism in leukemia cells We are currently investigating the post-translational regulation of a human BH3-only protein, Noxa, in hematological malignancies. Human Noxa in stably and constitutively expressed in a majority of leukemia cells and kept in check through post-translational control mechanisms. Interaction of Noxa with its pro-survival binding partner Mcl-1L plays a major role in the apoptotic response of proliferating lymphoid and myeloid leukemia cells to glucose deprivation. We show that, in the presence of adequate glucose, human Noxa is phosphorylated on serine13 by the cyclin dependent kinase, Cdk5, and sequestered within large multi-protein cytosolic particles (Lowman et al2010). Apoptotic triggers, particularly glucose limitation, dephosphorylate Noxa, unmasking its pro-apoptotic function. An understanding of how Noxa is post-translationally regulated will aid in the design of therapeutic strategies that target the modified protein and promote its release from sequestration. Paradoxically, modified sequestered Noxa stimulates glucose consumption and lactate production in T acute lymphocytic leukemia (T-ALL) cells. Our observations point to a novel 'survival' role for Noxa in regulating glucose metabolism in cancer cells; specifically our data point to a role for Noxa in the anabolic pentose phosphate pathway that is crucial for dividing cells. Additionally, we have identified the protein components of two Noxa/Mcl-1L-containing complexes from proliferating leukemia cells by mass spectrometry and are currently investigation their function. Noxa, a canonical tumor suppressor like other BH3-only proteins, had not previously been associated with a survival role. Our studies reveal Noxa as the second BH3-only protein, after family member BAD, to be attributed a metabolic function and underscore the intriguing possibility that other BH3-only members may hold day jobs as pro-survival proteins.

Publications

• Kelekar A and Jameson SC. CoAching CD8(+) T cells for tumor immunotherapy-the pantothenate way. Cell Metab 2021,33(12), 2305-2306.https://doi.org/10.1016/j.cmet.2021.11.009
• Matias MI, Yong CS, Foroushani A, Goldsmith C, Mongellaz C, Sezgin E, Levental KR, Talebi A, Perrault J, Riviere A, Dehairs J, Delos O, Bertand-Michel J, Portais JC, Wong M, Marie JC, Kelekar A, Kinet S, Zimmermann VS, Levental I, Yvan-Charvet L, Swinnen JV, Muljo SA, Hernandez-Vargas H, Tardito S, Taylor N, Dardalhon V. Regulatory T cell differentiation is controlled by aKG-induced alterations in mitochondrial metabolism and lipid homeostasis. Cell Rep. 2021 Nov 2;37(5):109911. doi: 10.1016/j.celrep.2021.109911
• Yan, Y., Krecke, K.N., Bapat, A.S., Yang, T., Lopresti, M.W., Mashek, D.G., and Kelekar, A.  Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK. Cell Death Dis 12, 904 (2021). https://doi.org/10.1038/s41419-021-04196-4
• Jemmerson, R., K. Staskus, L. Higgins, K. Conklin and A. Kelekar. Intracellular leucine-rich alpha-2-glycoprotein-1 competes with Apaf-1 for binding cytochrome c in protecting MCF-7 breast cancer cells from apoptosis. 2020. Apoptosis 26:71-82. 

Bio

Esther Krook-Magnuson is an Associate Professor in the Department of Neuroscience. Her work focuses on brain circuitry, including the different types of neurons in the brain and their responsiveness to drugs like opioids.

Research Summary

Selective Neuromodulation Neuronal networks, diversity, and specificity of function are important to both physiological processes and neurological disorders, including epilepsy. My laboratory seeks to improve our understanding of how cells interact within a network, how networks interact with each other, and the physiological roles of neuronal populations. In this regard, key questions remain in epilepsy research, including what are the principal networks, conditions, and cell types involved in initiating, sustaining, propagating, terminating, and potentially suppressing, seizures. By improving our understanding of these, we improve the prospects of someday reaching the goal of no seizures, no side effects, for all epilepsy patients. My lab uses rodent models of neurological disorders, including temporal lobe epilepsy, and techniques including electrophysiology, optogenetics, immunocytochemistry, transgenic animals, and behavioral experiments to address these fundamental questions

Bio

Dr. Lange is a Professor in the Departments of Medicine and Pharmacology at the University of Minnesota. She holds the Tickle Family Land Grant Endowed Chair of Breast Cancer Research. She received her PhD from the University of Colorado School of Pharmacy in 1991. She holds memberships in the American Association for Cancer Research (AACR), The Endocrine Society (ES) and Women in Endocrinology (WE). Dr. Lange serves as teaching faculty in the U of MN Department of Pharmacology Graduate Program, the Microbiology, Immunology, and Cancer Biology (MICAB) Graduate Program, the Genetics, Cell Biology, and Development (GCD) Graduate Program, and the MSTP (MD/PhD Combined) Program. She has served on several NIH Study Sections including Biochemical Endocrinology, Metabolic Physiology, Tumor Cell Biology, and Molecular Oncogenesis. She is on the Board of Scientific Advisors to the NIEHS. Dr. Lange is the Editor-in-Chief of the journal of Endocrinology (The Endocrine Society - Oxford Academic Journals)

Research Summary

The Lange Lab is focused on the role of steroid hormone receptors (SRs) in breast and ovarian cancers. Estrogen receptor (ER) and progesterone receptors (PRs) are ligand-activated and context-dependent transcription factors that are essential for development of the breast and reproductive tract. Altered sex hormone levels contribute to cancer risk in these tissues and drive metabolic and cell fate transitions associated with rapid tumor progression. The presence of abnormally activated ERs and imbalanced/activated PR and GR isoforms in hormone-driven tumors can dramatically influence response to endocrine or other therapies. Our overarching research goal is to better understand how SR+ breast cancers and other hormone-influenced cancers of reproductive tissues escape endocrine (i.e. SR-blocking) or other molecular targeted therapies that primarily target signaling pathways that are active in proliferating cancer cells.Ongoing projects encompass the following research themes and their molecular mechanisms:• ER and PR isoform signaling cross talk in luminal breast cancer progression• Ligand-independent actions of p-SRs and p-SR-containing complexes in breast cancer• Altered SR actions in the context of ESR1 mutations or BRCA1/2 loss or mutation• Cellular "stress" sensing by phospho-GR in triple negative breast cancer progression• Fallopian tube transformation and early SR+ serous ovarian cancer progression• Cell fate plasticity (cell cycle exit/entry into G0) and breast cancer stem cell biology• Mechanisms of and biological role of cancer cell dormancy/quiescence and senescence• SR and signaling pathway regulation of breast cancer stem cell populations and biology• Breast cancer metastatic cell dissemination as circulating tumor cell/stem cell clusters

Bio

Dr. Lee received her B.S. degree in Pharmacology from the University of Alberta in Edmonton, Canada, and her Ph.D. in Pharmacology from the University of Toronto. She then moved to the US for a post-doctoral fellowship with Dr. Robert Messing at UCSF. Dr. Lee was a Research Assistant Professor at the University of Texas, Austin, prior to moving to her current position in the Department of Pharmacology at the University of Minnesota.

Research Summary

The goal of my research is to elucidate the molecular basis of behavior. I am interested in the mechanisms that mediate alcohol and nicotine addiction separately, and those that are involved in alcohol and nicotine co-addiction. Alcohol and nicotine are two commonly used drugs, and addiction to both drugs is very prevalent. Alcohol and nicotine addiction have overlapping molecular mechanisms, and identifying these mechanisms will enable us to understand why these drugs are co-abused and to identify new molecular targets for treatment. We use a wide range of molecular and behavioral tools including transgenic mouse models, viral genetic manipulations, pharmacological tools and behavioral assays in mouse models of drug addiction.One major area of focus in the lab are the nicotinic acetylcholine receptors (nAChRs), and how different nicotinic receptor subtypes mediate aspects of co-addiction. These receptors are widely expressed ligand-gated ion channels that are primarily found on pre-synaptic terminals and on neuronal cell bodies, and thus are poised to modulate neurotransmission and regulate neural circuits. As such, nAChRs are implicated in alcohol and nicotine addiction, anxiety, depression and learning/memory. Our goal is to identify how different nAChR subtypes, and how regulation of nAChRs can affect neuronal activity, circuit function and behavior. We currently have several projects that focus on nAChRs in addiction: 1) Cholinergic regulation of alcohol aversion. A major project in our lab is to determine how the nAChRs mediate alcohol reward, aversion and consumption. Our recent work has uncovered a novel role for the nAChRs in alcohol aversion, and our goal is to identify the neuronal circuit and nAChR subtype that is involved. 2) Sex dependent regulation of nAChR gene expression. We recently discovered novel regulation of the alpha6 and beta3 nAChR subtypes by protein kinase C epsilon and sex hormones, resulting in oppositional expression of addiction-related behaviors in mice. Our goal is to determine how molecular regulation of these nAChR genes differs between sexes. 3) Altered abuse liability of electronic cigarette liquids. We are actively investigating whether the abuse liability of electronic cigarette liquid refills differs from nicotine alone, and whether this is modulated by flavors.

Bio

Julia Lemos is an Assistant Professor of Neuroscience and member of the University's Medical Discovery Team on Addiction. Her laboratory investigates how stress is processed and encoded in the brain. In particular, they interested in understanding how stress-associated neuropeptides regulate the function of neural circuits important for motivation and emotion in individuals with different life histories. Her laboratory also works to understand how chronic or traumatic stress renders the brain vulnerable to disease states such as depression, anxiety, and addiction.

Research Summary

Intuitively we know that stress can influence our decision-making process; this is part of our daily lives. While responding to acute stressors appropriately allows us to make good decisions, chronic or severe stress can lead to bad decision-making. These processes can be observed across many species, from rodents to humans. In humans, this switch in how we make choices following chronic stress can make an individual vulnerable to diseases like addiction or depression. Despite compelling motivations to study the influence of stress on decision-making, the neurobiology of how acute or chronic stress alters decision-making remains largely unexplored. To answer these questions, my laboratory uses a multi-disciplinary approach in which we pair conventional physiological and behavioral techniques with novel transgenic and optogenetic technology in mice. We use the information obtained from our ex vivo experiments to make predictions about the impact of stress and stress-associated on exploration, reward learning and decision-making behavior. Moreover, we can put our ex vivo observations to task by testing the causal relationship between our cellular and circuit findings and behavioral output. We often see how a life history of chronic or severe stress impacts normal functioning to shift behavioral outputs. Using this paradigm, we can then test whether different therapeutic interventions can reverse the impact of chronic stress on exploration and decision-making behaviors. 

Bio

Dr. Leung is an Assistant Professor of Pharmacology and a member of the Masonic Cancer Center's Cellular Mechanisms Program. He received a B.S. degree in Biochemistry at University of Maryland at College Park. Dr. Leung then received his Ph.D. from the Johns Hopkins University School of Medicine working with Randall Reed, Ph.D. in the Department of Molecular Biology and Genetics. He then moved to Harvard Medical School for his post-doctoral training with Joan Brugge, Ph.D. before joining the Department of Pharmacology at the University of Minnesota.

Research Summary

Research in the Leung Lab focuses on understanding the cellular and molecular control of cancer cell quiescence in the context of premalignant development, cancer treatments, and relapses. Our overarching goal is to identify early markers for cancer development and develop targeted approaches for treating residual disease and reducing cancer relapses. The laboratory focuses on breast cancer, but also studies other epithelial cancer types including lung and ovarian. Sustained quiescence despite genetic alterations supporting tumor growth is a common feature of premalignant cells and dormant cancer cells during cancer progression and under cancer treatments. The maintenance and outgrowth of such quiescent mutant cells underlie the checkpoints that control the latency of primary and recurrent cancer development. The Leung Lab develops 3D organotypic and animal models to recapitulate the genetic, cellular, and stromal environments of premalignant development and residual diseases. Utilizing these models as discovery platforms with diverse cellular and molecular techniques including genetic engineering, live-cell imaging, proteomics and high throughput screening, current studies in the laboratory focus on elucidating the roles of kinase signaling and epigenetic regulators in quiescent cancer cell survival and cell cycle control, and exploiting these controls to develop prognostic markers for residual diseases and therapeutic strategies for cancer relapses.

Bio

Dr. Levinson is an Associate Professor in the Department of Pharmacology and a member of the Masonic Cancer Center's Genetic Mechanisms Program. Dr. Levinson received his Bachelors and Masters degrees in Biochemistry from Cambridge University, and his PhD degree from the University of California, Berkeley, where he studied the structural basis of protein kinase function. After postdoctoral training at Stanford University in the Department of Chemistry, he joined the University of Minnesota as an Assistant Professor in 2014.

Research Summary

The Levinson Lab studies the structural and dynamic basis for protein kinase function. We use a diversified range of methods spanning crystallography, magnetic resonance, and ultrafast spectroscopy to dissect the role of kinase conformational dynamics in catalytic function and drug targeting. Our work has revealed the existence of dynamic water networks in kinase active sites that are important for catalytic function, and shown that large-scale conformational changes play a critical role in selective recognition of kinase inhibitor drugs. We have also shown that kinase engagement with different regulatory partners modulates these dynamic effects to alter inhibitor recognition. We aim to leverage these approaches and insights for the design of next-generation cancer therapeutics that modulate kinase allosteric functions by tuning conformational dynamics.

Bio

Please visit Dr. Fang Li's lab website for more information.

We study the structural and molecular basis of human diseases including virus infections, cancer and other human diseases.

Our main line of research examines the invasion mechanisms of viruses. We investigate the structures and functions of virus-surface proteins that mediate receptor recognition and cell entry of viruses.

Our other line of research explores the structural and molecular basis for cancer and other human diseases. Specifically, we investigate the structures and functions of human-cell-surface enzymes that are critical for disease mechanisms.

Based on these structural and functional studies, we further develop novel therapy strategies to treat human diseases.

Our research tools include X-ray crystallography, cryo-electron microscopy, protein biochemistry, and vaccine and drug designs.

Research Summary

Professor Li is a leading researcher in the coronavirus entry field, having determined many structures of coronavirus spike proteins and discovered the molecular events that lead to coronavirus entry into host cells. His research has been one of the major driving forces behind what we now know about receptor recognition and cell entry of coronaviruses. Moreover, he has developed structure-based strategies for vaccine design and drug development. His research provides foundational knowledge for the field of coronaviruses.

Furthermore, Professor Li's research on COVID-19 has elucidated how the pandemic virus infects cells while evading immunity and deciphered the evolution of COVID-19 variants, laying foundations for therapeutic development.

Currently Professor Li and his team are developing novel therapeutics against COVID-19 and improving the drug discovery process. In the long run, he would like to extend the scientific discoveries he made in the field of coronavirus to treat other viral infections and human diseases.

U researchers make key COVID-19 virus discoveries

Structure, Function, and Evolution of Coronavirus Spike Proteins

Receptor Recognition Mechanisms of Coronaviruses: a Decade of Structural Studies

Research Summary

Unfolded Protein Response in Neurological Diseases The research in my laboratory is focused on understanding the effects of the unfolded protein response on neurological diseases and their underlying mechanisms.Endoplasmic reticulum stress, initiated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum lumen, activates an adaptive program known as the unfolded protein response, which coordinates endoplasmic reticulum protein-folding demand with protein-folding capacity and is essential to preserve cell function and survival under stressful conditions. Nevertheless, the unfolded protein response also controls an apoptotic program to eliminate cells whose folding problems in the endoplasmic reticulum cannot be resolved by the adaptive response. In eukaryotic cells, three endoplasmic reticulum–resident transmembrane proteins involved in the unfolded protein response have been identified: pancreatic ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). It has become increasingly clear that endoplasmic reticulum stress is an important feature of a number of neurological diseases, such as myelin disorders, neurodegenerative diseases, and brain tumors. Due to the double-edged sword nature of the unfolded protein response, the role that the unfolded protein response plays in these diseases remains ambiguous.Our work utilizes sophisticated mouse models to dissect the precise role of individual branch of the unfolded protein response in myelin disorders, neurodegenerative diseases, and brain tumors. These studies could provide mechanistic insight necessary for designing novel therapeutic strategies for patients with these diseases.

Bio

Dr. Lipscomb received his B.S. degree from University of California Los Angeles with a degree in Microbiology, Immunology and Molecular Genetics prior to receiving a Ph.D. degree in Immunology from the University of Pittsburgh. His postdoctoral training was at University of Pennsylvania and Children's Hospital of Philadelphia. Prior to coming to the University of Minnesota in 2022, Dr. Lipscomb held a faculty position at Howard University.

Research Summary

Research in the Lipscomb Lab employs both basic and translational approaches to delineate the immunoregulatory networks that govern antigen presenting myeloid cell development and function. Specific focus is on defining the roles of novel genes that regulate dendritic cells (DC), monocyte and macrophage intracellular signaling events that include modulation of Ca2+ and cyclic nucleotides levels, activation and inactivation of protein kinases (i.e. PKC and PKA) and downstream post-translational modifications of NFkB/ERK related pathways. The overarching objective is to significantly increase the understanding of how DC and macrophages coordinate differentiation and immunity under steady-state vs. disease settings. In a related series of studies, the Lipscomb lab investigates how antigen presenting myeloid cells contribute to autoimmune disorders, with a chief focus on delineating the pathways directing type 1 diabetes (T1D) and intestinal bowel disease (IBD). Novel genes present in the MHC class III locus within the myeloid groups are studied to determine their collective contribution to initiating, sustaining and directing autoimmune pathologies. The laboratory employs conditional and global knockout mouse models to gain mechanistic insights into in vivo functional outcomes. This is often combined with use of viral and bacterial challenge studies and antigen-restricted mouse models (i.e. OT-I, OT-II) to evaluate immune responses in an antigen-specific manner upon pathogen exposure. Similarly, autoimmune mice models (i.e. NOD and Mdr1a-/-) are employed to best describe how key gene expression in MHC class III regions regulate chronic inflammatory states and autoreactive T cell responses.

Bio

Dr. Branden Moriarity is currently an Associate Professor in the Department of Pediatrics, Division of Hematology/Oncology. He graduated from Saint Olaf College in 2007 with a BA in Biology, Chemistry, and Biomolecular sciences. He received his PhD in Molecular, Cellular, Developmental Biology & Genetics at the University of Minnesota in 2012. From 2012-2014 he was a post doctoral fellow in David Largaespda's lab, where he worked on identifying the genetics of pediatric sarcomas. He joined the Department of Pediatrics Faculty in 2014.

Dr. Moriarity runs a basic/translational research laboratory working to develop novel cellular therapeutics for gene therapy and cancer immunotherapy with the goal of translating new therapeutics to the clinic. To accomplish these goals, the Moriarity lab uses cutting edge genome engineering technologies, including CRISPR/Cas9, base editor technology, transposons, and rAAV. These tools allow for high frequency gene knockout, gene knock-in, induction of targeted sequence changes, and activation and/or repression of endogenous gene expression. Target cells for engineering include T cells, B cells, NK cells, Monocytes, and hematopoietic stem cells. In addition to developing cellular based therapeutics, the Moriarity lab also performs preclinical drug testing for pediatric cancers, such as osteosarcoma, in order to launch new clinical trials using antibody therapies rather than toxic chemotherapy.

Administrator Information

Rick Jacobson
Administrative Email: rickj@umn.edu

Research Summary

Preclinical Drug Testing, Genome Engineering, Gene Therapy, and Cancer Immunotherapy.
Dr. Moriarity runs a basic/translational research laboratory working to develop novel cellular therapeutics for gene therapy and cancer immunotherapy with the goal of translating new therapeutics to the clinic. To accomplish these goals the Moriarity lab uses cutting edge genome engineering technologies including CRISPR/Cas9, base editor technology, transposons, and rAAV. These tools allow for high frequency gene knockout, gene knock-in, induction of targeted sequence changes, and activiation and/or repression of endogenous gene expression. Target cells for engineering include T cells, B cells, NK cells, Monocytes, and hematopoietic stem cells. In addition to developing cellular based therapeutics, the Moriarity lab also performs preclinical drug testing for pediatric cancers, such as osteosarcoma, in order to launch new clinical trials using antibody therapies rather than toxic chemotherapy. 

Bio

Dr. Nguyen is an EvansMDS Young Investigator, determining mechanisms and therapeutic strategies for Myelodysplastic syndrome patients harboring RNA splicing gene mutations. He is also a part of a multidisciplinary team in the functional genomics of solid tumors, launched by the Medical School and the Masonic Cancer Center to develop new technologies and models for understanding cancer heterogeneity. He received his B.A. degree from The College of Wooster, Ohio and Ph.D. degree from University of Minnesota in the laboratory of Dr. Anja-Katrin Bielinsky. He completed his postdoctoral research training in Dr. Lee Zou's laboratory at Harvard Medical School and Massachusetts General Hospital Cancer Center.

Research Summary

In response to DNA damage from environmental and endogenous sources, cells activate an elaborate signaling network called DNA damage response (DDR). This response functions to preserve genomic integrity, which is critical for normal development and cancer prevention. The ATR kinase is a master regulator of a broad spectrum of DNA damage and replication problems.Sensors of DNA Damage, Replication and Transcription Problems: Our recent studies revealed that ATR is not only important for sensing DNA damage and replication stress, but also to problems associated with transcription. R-loop, a transcription intermediate resulting from the formation of stable RNA:DNA hybrids and a displaced single-stranded DNA (ssDNA), is a major source of genomic instability. We found that ATR is activated by R-loops and plays a critical role in suppressing R-loop-induced genomic instability, thus uncovering a new function of ATR in maintaining genome integrity. The Nguyen laboratory will continue to dissect how ATR regulates R-loop resolution in cancers. Cancer Genomics and Targeted Therapy: we found that the splicing factor mutations associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) induce R-loops and trigger an ATR response. Cells that express these splicing factor mutants are sensitive to ATR inhibitors, providing a new strategy to target R-loop response for the treatment of MDS and potentially other malignancies associated with RNA splicing mutations. The Nguyen laboratory will determine additional R-loop regulators in different cancer contexts to develop new therapeutic strategies in the future. The Nguyen laboratory is currently developing small molecule probes, biochemical, cell biological and genetic approaches to investigate the underlying mechanisms of sensing and resolving R-loops in different cancers. Results obtained from these researches will provide molecular insight for the development of new targeted cancer therapeutic approaches. Interested applicants should have a PhD and/or MD degree with a strong background in either biochemistry, cell biology, functional genomics, or pharmacology. The laboratory accepts Master and PhD students through Department of Pharmacology program. 

Research Summary

My research career has been dedicated to investigating the impact of DNA damage on the structure of DNA, cell function and organism health. The DNA in each of our cells is damaged thousands of times per day by exposure to environmental factors, dietary components, chemotherapeutic agents and even endogenous by-products of normal metabolism. Studying patients with rare diseases caused by inherited defects in DNA repair provides important insight into the consequences of DNA damage. These patients have a dramatically increased risk of cancer and age prematurely. We engineered mouse models of these genome instability syndromes as a sensitive tool to test hypotheses about how DNA damage promotes cancer and aging.

Research Summary

Our laboratory focuses on G-protein coupled receptor (GPCR) signaling in the heart, with two main areas of emphasis.
1. Free fatty acid receptor 4 (Ffar4). Ffar4 is a G-protein coupled receptor for long chain fatty acids (Carbon chains 14-24) including omega-3 polyunsaturated fatty acids (omega 3-PUFAs). Clinically, omega 3-PUFAs improve outcomes in heart failure, but the mechanism is unclear. We previously demonstrated that eicosapentaenoic acid, or EPA an omega 3-PUFA, prevents heart failure in a mouse model but not through the traditional mechanism of membrane incorporation. Alternatively, we found that the cardioprotective effects of EPA might be mediated through Ffar4, an entirely novel molecular mechanism to explain the benefits of omega 3-PUFAs in the heart. Currently, our research is focused on understanding this novel role for Ffar4 as a cardioprotective nutrient sensor in the heart that responds to fatty acid composition to protect the heart from pathologic stress.
2. alpha 1-Adrenergic receptors (alpha 1-AR): alpha 1-ARs are receptors activated by the endogenous sympathetic catecholamines norepinephrine (produced in sympathetic nerve terminals) and epinephrine (produced in the adrenal gland). Clinically, alpha 1-ARs were originally used for the treatment of hypertension (HTN) and are currently used to treat benign prostatic hyperplasia (BPH). Clinical trials demonstrated that alpha 1-AR antagonists (doxazosin) worsened outcomes in patients with HTN, significantly increasing cardiac events and doubling the risk of heart failure. Our work has provided a mechanistic basis to explain the failure of alpha 1-blockers in patients with HTN, demonstrating that alpha 1-ARs in cardiac myocytes protect the heart from pathologic stress. Currently, our research is focused on understanding the molecular basis for the cardioprotective effects of alpha 1-ARs focusing on how differential subcellular compartmentalization of receptors affects their function. Further, based on our work on alpha 1-AR subcellular compartmentalization, we are developing a next-generation alpha 1-blocker for HTN without cardiac side-effects.

Bio

Administrator Info
Lab Phone: 612-624-8201
Phone: 612-626-5475
Email: mccadmin@umn.edu
Mail: Cancer and Cardiovascular Research Building
1st Floor Mailroom CCRB
2812A (Campus Delivery Code)
2231 6th St SE
Minneapolis, MN 55455

Summary
Julie Ostrander, Ph.D. is an Assistant Professor in the Department of Medicine at the University of Minnesota and a member of the Cellular Mechanisms of Cancer Program at the University of Minnesota Masonic Cancer Center. Dr. Ostrander received her Ph.D. from the University of North Carolina at Chapel Hill. She holds memberships in the American Association for Cancer Research and the Endocrine Society.

Research Summary

Dr. Ostrander's research focuses on studying the scaffolding protein PELP1 in the context of breast cancer progression. Our recent studies have found that PELP1 signaling 1) promotes cell survival in the presence of tamoxifen, 2) enhances breast epithelial cell migration through upregulation inflammatory cytokines and chemokines, and most recently 3) promotes CSC phenotypes in models of ER-positive breast cancer. We have identified a novel cytoplasmic interaction between PELP1 and SRC-3. The objective of our current research is to identify the molecular mechanisms associated with PELP1-induced BCSC phenotypes and therapy resistance.

Research Summary

The pathways important for driving autoimmune and inflammatory diseases as well as age related degeneration are surprisingly similar. For example, inhibition of the transcription factor NF-?B is therapeutic in mouse models of autoimmunity and inflammation as well as Duchenne muscular dystrophy and aging. Similarly, inhibition of IL-1ß signaling by gene transfer of the IL-1 receptor antagonist protein is therapeutic in multiple models of diseases. The Robbins laboratory is developing novel approaches to treat autoimmune (type 1 diabetes, rheumatoid arthritis), inflammatory (inflammatory bowel disease, delayed type hypersensitivity) and age-related degenerative diseases using biologics and small molecules. The therapeutic approaches being developed include: 1) AAV mediated gene transfer of anti-inflammatory or immunosuppressive agents; 2) Peptide and small molecule inhibitors of the transcription factor of NF-?B; 3) Novel osteogenic peptides; 4) Adult stem cells; 5) Microvesicles (exosomes) derived from immunoregulatory or stem cells able to block inflammation or promote regeneration; and 6) Identification of drugs able to reverse cellular senescence for improving healthy aging. Although the majority of the studies are being performed in mouse models of disease, approaches to treat osteoarthritis by intra-articular AAV-mediated gene transfer and Duchenne muscular dystrophy by systemic treatment with a NF-?B inhibitory peptide will soon be entering the clinic.

Bio

Patrick Rothwell is an Assistant Professor in the Department of Neuroscience. His research lab investigates the synaptic organization and behavioral function of basal ganglia circuits in health and disease. His interests include regulation of these circuits by endogenous opioid signaling, as well as the detrimental effects of chronic exposure to exogenous opioids, with a broad goal of reducing the abuse liability of opioid-based clinical therapies.

Research Summary

Modulation of striatal circuits in health and disease Brain disorders and mental illness represent a tremendous social and economic burden, with few effective treatments. The goal of our research is to identify the causes of brain conditions, and develop interventions to restore healthy function using synaptic plasticity and neuromodulation. We study the striatum, and important brain region for both simple and complex movements and cognitive functions. The striatum contains a variety of cell types, which receive synaptic input from many different sources and relay information through the basal ganglia. We examine the function of neural circuits formed by striatal synapses that connect specific sources and targets. Our multidisciplinary approach includes quantitative analysis of gene expression; genetic and molecular manipulations of neural circuits; measurement of synaptic function and plasticity using electrophysiology; and optogenetic stimulation of circuits in brain slices and behaving animals. Our current research focuses on autism spectrum disorders and drug addiction - two brain conditions that affect overlapping elements of striatal circuitry.

Bio

Dr. Ruan received his Ph.D. in Genetics from Nanjing University in 2008. He then did his postdoctoral training at Yale University School of Medicine from 2009 to 2015. In January 2016, he started his independent research lab at the Department of Integrative Biology & Physiology of University of Minnesota Medical School.

Research Summary

The research in my laboratory is directed towards understanding how environmental cues and intrinsic signals are integrated to regulate metabolic processes in health and disease. The Ruan laboratory currently conducts an integrated program in the following directions on tissue adaptation and remodeling upon metabolic stress: (1) protein O-GlcNAcylation in physiology and disease, (2) adipose Biology remodeling and energy balance, (3) intestinal epithelium at the interface between gut microbes and host physiology, and (4) immune homeostasis and its regulation of systemic metabolism. Using an integrative approach, we aim to define the pathological alterations of metabolic communication in diseases including obesity, diabetes, inflammation, and aging. Ultimately, we hope to identify targets and to design therapeutics for these diseases.

Bio

Administrator Info
Phone: 612-626-5475
Lab Phone: 612-626-5045
Email: mccadmin@umn.edu
Mail: Cancer and Cardiovascular Research Building
University of Minnesota
1st Floor Mailroom CCRB
2812A (Campus Delivery Code)
2231 6th St. S.E.
Minneapolis, MN 55455

Summary
Dr. Sachdev is a member of the Cellular Mechanisms Program of the Masonic Cancer Center. She received her Ph.D. from the University of Texas Health Science Center at San Antonio. She holds memberships in the American Association for Cancer Research and the Endocrine Society.

Research Summary

Dr. Sachdev's research interests focus on the regulation of breast cancer biology by growth factors such as insulin-like growth factors, growth factor targeted therapy for breast cancer, and development of biomarkers for growth factor-targeted therapy. Her laboratory is examining the use of non-invasive magnetic resonance imaging and spectroscopy and gene array signatures to predict and monitor response to inhibition of insulin-like growth factor signaling in breast cancer cell growth and metastasis. She is also examining the mechanisms by which insulin-like growth factors regulate metastasis of breast cancer cells using animal models of metastasis and in vivo imaging.

Research Summary

Dr. Schwertfeger is a member of the Division of Molecular Pathology and Genomics.  Her main research effort is focused on the breast cancer microenvironment and how breast cancers cells interact with cells in the stroma, particularly with immune cells. The cell of particular interest to her group is the macrophage, a specialized innate immune system cell. Macrophages circulate as monocytes in the blood and are recruited to different tissue sites as part of an immune response. Macrophages have long been known to be associated with tumors, initially it was thought to attack tumors. More recently scientists have found that macrophage populations at a tumor site is reflective of tumor size and aggressiveness, suggesting the possibility that macrophages may serve to promote tumor growth rather than attacking tumors. It is now understood that macrophages are recruited by tumors through signaling mechanisms and commandeered to assist in tumor expansion and metastasis.Schwertfeger and her colleagues are interested in the mechanisms that drive macrophage-tumor cell interactions and the internal signaling in macrophages that causes them to respond the way they do in the tumor microenvironment. If signaling mechanisms can be identified, they could be targets for therapeutic intervention. Macrophages, literally "big eaters," are large cells that normally engulf and digest cellular debris and foreign material and could potentially be turned against the tumor. Researchers have tended to focuses on the soluble growth factors macrophages produce as part of their normal functions rather than signaling pathways that could reveal how and why they produce these factors. Schwertfeger's team is currently exploring three macrophage signaling molecules involved in normal macrophage functioning and that of other cell types. They include two transcriptions factors, STAT3 and STAT5, and the cell-surface enzyme ADAM17, which is involved in a spectrum of regulatory activities that includes cleaving of cell-surface-bound growth factors, freeing them to carrying out their cellular functions. Schwertfeger and her colleagues have found that activation of the fibroblast growth factor receptor (FGFR)-STAT3 pathway induces accumulation of the extracellular matrix carbohydrate hyaluronan, which promotes tumor proliferation and migration. Although drugs targeting STAT transcription factors or ADAM17 enzymes are plausible, how inhibiting these pathways would affect immune system function in healthy and tumor tissue is unknown and is a related research interest of Schwertfeger's laboratory.Schwertfeger's laboratory is also exploring how breast cancer cells interact with osteoclasts to promote bone metastasis using the FGFR signaling pathway. The research is trying determine whether the pathway is important in the ability of breast cancer cells to activate osteoclasts, initiate bone degradation and form osteolytic breast cancer lesions. The FGFR pathway can be targeted, with a number of inhibitors currently in clinical trials for treating primary tumors but not metastasis. Schwertfeger's goal is to see whether the FGFR pathway inhibitors can be used to inhibit breast cancer metastasis._ _Member, American Association for Cancer Research (AACR) NIH/NCI Grant Review Panel: Member of Tumor MicroEnvironment study sectionJournal of Mammary Gland Biology and Neoplasia - Editorial Board MemberBreast Cancer Research - Associate Editor

Publications

• Irey EA, Lassiter CM, Brady NJ, Chuntova P, Wang Y, Knutson TP, Henzler C, Chaffee TS, Vogel RI, Nelson AC, Farrar MA, Schwertfeger KL. JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors. Proc Natl Acad Sci U S A. 2019 May 30. pii: 201816410. doi: 10.1073/pnas.1816410116. 
• Nelson AC, Machado HL, Schwertfeger KL. Breaking through to the other side: Microenvironment contributions to DCIS initiation and progression. J Mammary Gland Biol Neoplasia. 2018 Aug 31. doi: 10.1007/s10911-018-9409-z. 
• Farooqui, M., Bohrer, L.R., Brady, N.J., Chuntova, P., Kemp, S.E., Wardwell, C.T., Nelson, A.C. and Schwertfeger, K.L. Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival. Molecular Cancer. 14(138), 2015. PMID: 26215578.

Research Summary

Understanding the dynamics of how growth-promoting mutations arise and accumulate in a population of cells is a fundamental problem underlying our understanding of drug resistance, tumorigenesis, and the treatment of cancer. We use experimental evolution, mathematical modeling, and comparative genomics to understand the impact of mutations on the adaptation of a cell and its surrounding population.We employ diverse yeast model systems (Saccharomyces cerevisiae, Candida albicans, Candida auris, etc.) to understand how genome instability contributes to adaptation (eg. antifungal drug resistance) and determine the underlying mechanisms that promote genome instability. In the human fungal pathogen Candida albicans, genome rearrangements resulting in copy number variation (CNV) and loss of heterozygosity (LOH) confer increased virulence and antifungal drug resistance, yet the mechanisms driving these rearrangements are not completely understood. We recently identified an extensive array of long repeat sequences (65–6499 bp) that are associated with CNV, LOH, and chromosomal inversions and are a significant source of genome plasticity across diverse strain backgrounds - including clinical, environmental, and experimentally evolved C. albicans isolates. Many of these long repeat sequences were uncharacterized and encompass one or more coding sequences that are actively transcribed. Further, the repeats associated with genome rearrangements were predominantly inverted and separated by up to ~1.6 Mb, an extraordinary distance for homology-based DNA repair/recombination in yeast!We also utilize flow cytometry-based systems that enable us to detect the acquisition and spread of beneficial mutations within populations. We found that polyploid S. cerevisiae adapted more rapidly than isogenic haploid or diploid cells in poor carbon medium, and that polyploid cells acquired more mutations, including point mutations, large segmental aneuploidies, and whole chromosome aneuploidies (Selmecki et al., Nature 2015). Additionally, polyploid cells acquired a broader spectrum of beneficial mutations than lower ploidy cells (Scott et al., MBE 2017). We continue to use these ploidy lineages to study how changes in chromosome number (ploidy and aneuploidy), cell size, and environment affect genome stability and evolvability. Our previous research identified chromosome aneuploidy as a driver for the acquisition of antifungal drug resistance in the pathogenic yeast C. albicans (Selmecki et al., Science 2006). We found that aneuploid cells arose within a population very rapidly in the presence of antifungal drug (Selmecki et al., PLoS Genetics 2009), and that increased copy number of two specific genes found on the most common aneuploid chromosome provided the drug resistance phenotype (Selmecki et al., Molecular Microbiology 2008).

Bio

Dr. Sheedlo attended Michigan State University where he received a B.S. in Biochemistry and Molecular Biology, awarded by Lyman Briggs College. He then transitioned to Purdue University where he earned his PhD from the Department of Chemistry, working in the laboratory of Dr. Chitta Das. After completing his PhD, he obtained a postdoctoral fellowship at Vanderbilt University Medical Center, working under the mentorship of Dr. Borden Lacy. Dr. Sheedlo joined the Department of Pharmacology as an Assistant Professor in 2021.

Research Summary

Research in the Sheedlo lab is focused on defining the mechanisms that govern interactions at the host-pathogen interface. Specifically, we are interested in using structural biology (cryo-electron microscopy and X-ray crystallography) to obtain a framework that we can then probe in a physiologically relevant context. Of particular interest is understanding how the Gram-positive pathogen, Clostridioides difficile, uses toxins and effectors to elicit disease. In this vein, we are actively pursuing two areas of research (described below).The Clostridioides difficile TransferaseA primary focus in the Sheedlo lab is an understudied toxin secreted by C. difficile known as the C. difficile transferase (CDT) or binary toxin. Although CDT is not found in all strains of C. difficile, it is produced by some of the most common clinical isolates. The presence of CDT in these strains has led to the hypothesis that the activity associated with CDT may lead to more severe disease outcomes. In the Sheedlo lab, we are interested in elaborating upon the mechanisms used by CDT to intoxicate host cells with the aim of better understanding the role that CDT plays during infection. Through our work, we intend to build upon foundational studies that have defined the structure of CDT and have highlighted features distinct from distantly related toxins such as anthrax toxin.Gram-positive Type Four Secretion SystemsA second project in the Sheedlo lab aims to improve our understanding of how type four secretion system (T4SS) machinery is arranged and utilized in Gram-positive bacteria. Although T4SSs can be evolutionarily linked to DNA conjugation, several pathogens have evolved to use these complex machines to their advantage during infection. In the Sheedlo lab, we are specifically interested in exploring the utility of a series of T4SS gene clusters recently identified in several strains of C. difficile. Ultimately, our goal is to better understand how C. difficile employs these T4SSs to interact with its environment.

Bio

Dr. Slosky is an Assistant Professor in the Department of Pharmacology and a member of the Medical Discovery Team on Addiction, a multidisciplinary initiative within the University of Minnesota's Medical School to advance research and treatment in the field of drug addiction. Dr. Slosky's research is focused on understanding how neuropeptide G protein-coupled receptors regulate reward, pain, and motivated behavior – and how these receptors can be targeted for therapeutic benefit. She is currently working to identify novel strategies for the treatment of stimulant and opioid addictions, with a focus on the development of allosteric and functionally selective small molecules. Dr. Slosky was awarded a B.S. with honors in Molecular and Cellular Biology and Psychology from The University of Arizona in 2011. She received a Ph.D. in Medical Pharmacology from The University of Arizona in 2015, under the mentorship of Dr. Todd W. Vanderah. Dr. Slosky completed a postdoctoral fellowship in the laboratory of Dr. Marc G. Caron at Duke University and joined the Department of Pharmacology as an Assistant Professor in 2021.

Research Summary

Substance use disorders are complex neurobehavioral pathologies for which there are a lack of effective therapeutics. The long-term goals of our research group are to expand our understanding of the biological basis of stimulant and opioid addictions and to develop mechanism-based pharmacotherapies for their treatment. In pursuit of these goals, we are working at the interface of receptor biology, behavioral pharmacology, and systems neuroscience.

Bio

Dr. Spencer is an Assistant Professor in the Department of Pharmacology. Dr. Spencer received her B.S. degree from the University of Alabama, Tuscaloosa in Biology in 2006. She received her Ph.D. degree in the Neuroscience Graduate Program from the University of Texas Southwestern Medical Center in Dallas in the laboratory of Dr. Colleen A. McClung. Her postdoctoral training was in the laboratory of Dr. Peter W. Kalivas at the Medical University of South Carolina. Dr. Spencer was recruited to the University of Minnesota as part of the Medical Discovery Team on Addiction.

Research Summary

Research in the Spencer Lab is motivated by understanding the mechanisms related to the development of addiction as a relapsing, remitting brain disorder in order to guide the rational design or discovery of new, more effective treatments for drug addiction. Chronic drug use results in a variety of maladaptive neuroadaptations that set the stage for relapse even after protracted abstinence periods. It is our hope that a better understanding of the trajectory of the neuroplasticity, physiology, and neurochemistry that underlie behavior will help guide these pursuits. The Spencer Lab uses preclinical rodent models of reward and other related psychiatric domains to achieve this goal. We couple this behavioral analysis with molecular, pharmacological, and genetic tools We have a major focus on glutamate and dopamine interactions within the primary reward circuitry (ventral tegmental area, prefrontal cortex, nucleus accumbens). We aim to validate a specific role of mesolimbic dopamine in controlling key biological adaptations at glutamatergic synapses in the nucleus accumbens that underlie cue-induced relapse to cocaine use. We are using viral mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics to activate and silence ventral tegmental area dopamine neurons during behavior. It remains to be seen what impact repeated drug relapse events are having on circuit function or long-term treatment outcomes, and our model will allow us to probe this question in the context of this circuit. We are also exploring novel pharmacological interventions for cocaine relapse including efforts to repurpose other FDA-approved drugs.Additionally, we are studying mechanisms of cannabinoid reward. Cannabis is the most widely used illicit drug worldwide, but enduring health consequences of its use are largely unknown. Delta-9-tetrahydrocannabinol, the primary psychoactive component of cannabis, displays a narrow dose reward window but produces enduring neuroadaptations following chronic self-administration that resemble other drugs of abuse. As with other drugs of abuse, THC can dose-dependently produce both reward and aversion. Understanding how each is encoded will help guide development of therapeutics for treating cannabis use disorder as well as designing non-addictive cannabinergic therapies for other disorders.

Bio

Dr. Laura Stone is a professor in the Department of Anesthesiology at the University of Minnesota. She received a Bachelor of Science in biochemistry from the University of California-San Diego and PhD in neuroscience from the University of Minnesota.

Research Summary

Dr. Stone's research interests include the mechanisms of pain, epigenetic regulation of chronic pain, and pharmacological and non-pharmacological methods of treatment.

Research Summary

Cancer immunology and immunothereapy; T cell engineering The Stromnes laboratory is focused on advancing the understanding of cancer immunology and immunotherapy, with a particular emphasis on properties of the tumor and the tumor microenvironment that influence antigen-specific T lymphocyte migration and function. The laboratory aims to uncover how tumors and their mutations coordinate a suppressive microenvironment and elicit a program of T cell dysfunction. The lab is also focused on understanding the cellular and acellular components of tumor microenvironment that influence immunotherapy response. The laboratory combines studies of human tumors, genetically engineered mouse models that faithfully recapitulate human cancer, and novel cell engineering approaches evaluated in both mouse and human T cells to develop next generation cellular therapies for intractable malignancies, with a major focus on carcinomas including pancreatic cancer. Preclinical studies performed by Dr. Stromnes and colleagues have led to a novel engineered T cell therapy for pancreatic and ovarian cancer patient treatment.

Bio

Administrative Contact: Kelli Tourand |  612-624-4581 | toura018@umn.edu

Our lab focuses on understanding the molecular mechanisms that regulate anti-tumor immune response in cancers. Currently we are investing the following topics in our laboratory.

1. Tumor derived extracellular vesicles and anti-tumor immunity in colorectal cancerAtypical chemokine receptor 4 (ACKR4) in anti-tumor Iimmunity in colorectal cancer MicroRNAs mediate host-microbiome interactions in colorectal cancer progressionRegulation of host immune response in osteosarcoma

Research Summary

MicroRNA mediated gene regulation in human sarcomasGene expression profiles - developing novel diagnostic markers and identification of therapeutic targets in sarcomas and other cancers. 1. Tumor derived extracellular vesicles and anti-tumor immunity in colorectal cancer. Colorectal cancer (CRC) remains the third most common cause of cancer-related deaths in the U.S. The majority (~85%) of CRC tumors are non-immunogenic, i.e. they lack a significant number of infiltrating T cells, and are typically unresponsive to the immune-checkpoint inhibitor based therapies that have dramatically changed the way we treat many cancer patients. T cells isolated from non-immunogenic, microsatellite stable (MSS) CRC have lower levels of the CD28 protein, which provides a co-stimulatory signal required for T cell activation, trafficking, proliferation, differentiation and cytotoxic activity. We are testing the following hypothesis that extracellular vesicles (EVs) containing immunosuppressive microRNAs secreted by CRC cells suppress host T cell activity locally and in tumor draining lymph nodes, resulting in a deficient immune response that allows for increased tumor progression and growth. Results from this study will fundamentally advance our knowledge of how cancer cells modulate and suppress the immune response, provide novel targets, and form the basis for a new anti-cancer therapeutic strategy. 2. Atypical Chemokine Receptor 4 (ACKR4) in anti-tumor immunity in colorectal cancer Several chemokines and cytokines are implicated in CRC immune response. One of the under examined features of CRC is the regulation of anti-tumor immunity by atypical chemokine receptor 4 (ACKR4) expression. This receptor, is involved in the internalization and degradation of multiple chemokines, such as chemokine (C-C motif) ligand 19 (CCL19) and CCL21, thereby modulating the CC-chemokine receptor 7 (CCR7)/CCL19/CCL21 chemotaxis and its downstream immune responses. We are testing the hypothesize that ACKR4 positively affects immune regulation in CRC and confers antitumor immunity by modulating CCR7/CCL19/CCL21 chemotaxis.The results from this pilot study will establish the clinical significance of ACKR4 expression levels to immune response in colorectal cancer. As an outcome, it will fundamentally advance our knowledge of how anti-tumor immunity was generated and regulated in CRC, and provide novel targets for CRC immunotherapies. 3. MicroRNAs mediate host-microbiome interactions in colorectal cancer progression The current standard of care for colorectal cancer (CRC) involves chemotherapies developed more than 50 years ago. Although the 5-year survival rate has been rising over the past few decades, it is still low at about 65%. And most of the improvement in survival is due to increased screening, which has identified more cases of CRC in earlier stages. In the past decade, with the advancement of high-throughput "omics" technologies, it has become clear that the microbiome plays an essential role in driving the pathogenesis of CRC; however, the mechanisms that underlie host-microbiome interactions in CRC have yet to be elucidated. Part of the reason is the complex interplay between the colon epithelium, the microbiome, and the immune system. Previous publications have elucidated how the microbiome could affect miRNA expression in CRC, but how CRC could affect the microbiome is not yet understood, even though host genetics is known to shape the microbiome. In light of these evidence, we are testing the hypothesis that a positive feedback loop exists in CRC in which preexisting dysbiosis initially drives the expression of certain miRNAs in the colon epithelium, which are then released into the colon lumen and in turn affect the composition of the gut microbiome, leading to additional dysbiosis. Results from this study will elucidate the underlying mechanisms of host-microbiome interactions in CRC and will provide insights into the development of novel treatment strategies. 4. Regulation of host immune response in osteosarcoma Osteosarcoma (OS) is the most common primary bone malignancy, accounting for ~2% of childhood cancers. The relative 5-year survival rate for patients <30 years is ~60%, for patients with metastatic OS the rate drops to <20% - rates that have not changed over the last three decades. There is a critical need to develop novel therapeutic strategies for OS. Immunotherapy is dramatically changing how we treat patients with cancer, however, it is only effective when immune cells are actively recognize and fight the cancer. Our previous work provided evidence that OS tumors show differing levels of immune cell infiltration, and that low levels of immune cell gene expression are strongly associated with metastasis and poor patient survival. We have identified a set of microRNAs whose expression also correlates with poor survival. Our central hypothesis is that lack of a robust immune response and disruption of miRNA-mediated signaling networks are two key factors contributing to OS progression, response to therapy, and patient survival outcomes. We have mRNA and microRNA sequence data for 55 human OS tumors, 20 of which will be further tested using histochemistry to reveal which tumors have active immune cell infiltration. This project will validate our novel expression-based method for identifying patients who have an active anti-tumor immune response, and are thus most likely to benefit from adjuvant immunotherapy. Our integrated expression analysis should validate novel therapeutic targets and advance our understanding of OS pathobiology, particularly the molecular mechanisms used by tumors to suppress the host immune system. These results are expected to have a positive translational impact as this knowledge will aid in the identification of novel therapeutic targets and inform future treatment and detection strategies, thereby improving the overall survival of osteosarcoma patients.

Bio

Dr. Thayer is a professor of pharmacology. He received BS degrees in Biology and Chemistry and a PhD in Pharmacology from the University of California at Irvine. After completing postdoctoral training at the University of Chicago in 1989, Dr. Thayer joined the faculty at the University of Minnesota.

Research Summary

Dr. Thayer's laboratory studies neurodegenerative processes. His group uses electrophysiological and optical techniques to measure ion currents, to image synaptic proteins and to record changes in intracellular calcium within single neurons. Current research efforts focus on three principal areas.1.Synapse loss occurs early in neurodegenerative disease and correlates with cognitive decline in patients with HIV-associated neurocognitive disorder and Alzheimer's disease. Recent studies indicate that loss of synapses is not a symptom of the cell's demise but instead, is a coping mechanism to reduce excess excitotoxic input. Current studies evaluate pharmacological strategies to prevent loss or induce recovery of synapses during neurotoxic processes.2.Calcium is an essential second messenger involved in neurotransmitter release, gene regulation, and synaptic plasticity. Inappropriate elevation of the intracellular calcium concentration contributes to the neurodegeneration associated with AIDS, ischemia, epilepsy and head trauma. Thus, neurons have developed a complex system to maintain calcium homeostasis. Current studies focus on the modulation of processes that remove calcium from the cytoplasm by drugs and second messengers.3.Cannabinoids, analogs of the psychoactive ingredient in marijuana, act on receptors that are part of an endogenous signaling system. Endocannabinoid signaling serves as an on-demand neuroprotective mechanism. Currents studies examine the role of the endocannabinoid system in regulating synaptic transmission and neurotoxicity.Drugs to slow the progression of neurodegenerative disease are lacking. Agents that modulate calcium signals, possibly via the endocannabinoid system, may protect synapses and cells from neurotoxic insult.

Bio

Dr. Thomas is a clinical chemist and a faculty member of the Advanced Research and Diagnostics Laboratory (ARDL) and a member of the Masonic Cancer Center. She is also the Associate Medical Director of the West Bank Laboratory. Motivated by the growing prevalence of mass spectrometry in the clinical laboratory, Thomas applies discovery and targeted proteomics methods to elucidate the biology of ovarian cancer and analyze proteins derived from alterations in cancer genomes and related biological processes.  Dr. Thomas is a member of the graduate faculty of Molecular Pharmacology and Therapeutics (MPaT); Biochemistry, Molecular Biology, and Biophysics; and Microbiology, Immunology and Cancer Biology (MICaB).

Research Summary

• Mass spectrometry
• Clinical proteomics
• Analytical chemistry

Thomas Research Lab

Publications

PubMed articles list

• Thomas, S.N., French, D., Jannetto, P.J., Rappold, B.A., and Clarke, W. A. Liquid chromatography–tandem mass spectrometry for clinical diagnostics. Nat Rev Methods Primers 2, 96 (2022). https://doi.org/10.1038/s43586-022-00175-x.
• Figueiredo JC, Hirsch FR, Kushi LH,.... Karger AB, Thyagarajan B, Thomas SN, ... Skarbinski J.  Mission, organization, and future direction of the Serological Sciences Network for COVID-19 (SeroNet) epidemiologic cohort studies. Open Forum Infect Dis. 2022 Apr 27;9(6):ofac171. doi: 10.1093/ofid/ofac171.
• Karger AB, Brien JD, Christen JM, Dhakal S, .... Thomas SN, Thyagarajan B, Wajnberg A, Yates JL, Sobhani K. The Serological Sciences Network (SeroNet) for COVID-19: Depth and breadth of serology assays and plans for assay harmonization. mSphere. 2022 Jun 15:e0019322. doi: 10.1128/msphere.00193-22. 
• Chaudhry S, Thomas SN, Simmons GE Jr.Targeting lipid metabolism in the treatment of ovarian cancer.
  Oncotarget. 2022 May 25;13:768-783. doi: 10.18632/oncotarget.28241. eCollection 2022.
• Thomas SN, Karger AB, Altawallbeh G, Nelson KM, Jacobs DR Jr, Gorlin J, Barcelo H, Thyagarajan B. Ultrasensitive detection of salivary SARS-CoV-2 IgG antibodies in individuals with natural and COVID-19 vaccine-induced immunity.  Sci Rep. 2022 May 25;12(1):8890. doi: 10.1038/s41598-022-12869-z 
• Ryu J, Thomas SN.  Quantitative mass spectrometry-based proteomics for biomarker development in ovarian cancer.  Molecules. 2021 May 3;26(9):2674. doi: 10.3390/molecules26092674.
• Murthy V, Altawallbeh G, Larson-Nath C, Karger AB, Thomas SN. Transient hyperphosphatasemia following pediatric liver transplantation in a patient with hepatic and skeletal abnormalities.  Clin Chim Acta. 2021 Apr 4:S0009-8981(21)00115-7. doi: 10.1016/j.cca.2021.03.030. 

Research Summary

The goal of our laboratory is to advance the field of cancer by genetically engineering and testing new biological drugs against chemotherapy refractory cancer. These new drugs kill by a mechanism entirely different than chemotherapy. We believe that we are in a unique position to address some of the most pressing issues including the engagement of the innate immune system to kill cancer. A new genre of drugs show that cancer metastasis can effectively be combated by engaging the immune system to selectively kill tumors. We developed a new drug platform that works extremely well in recruiting NK cells to kill leukemia cells. In addition to my conventional laboratory, I am fortunate to have a cGMP laboratory that manufactures FDA compliant drugs for phase 1 testing. We published our first clinical trial with one of these drugs in Clinical Cancer Research. We have an accomplished team of experts that can help this integrated effort succeed. Our laboratory has an established track-record in animal models and I have a background in immunology, experimental therapeutics, molecular biology, radiation oncology, and gene therapy that has served us well. Over the last 35 years, I have built my career and reputation on cell selective drug targeting and am recognized as a major contributor to the field. My immunology and molecular biology background has served me well and my team has published over a hundred and eighty PubMed papers. Our success in translational research is evidenced by our bringing targeted drugs to phase 1 clinical trial. The most recent targeted toxin will now enter phase 2 testing. We currently have active INDs and are treating patients at the University of Minnesota Cancer Center. I have a demonstrated a record of successful and productive research projects in an area of translational, biological drug development and serve as inventor on several patents held by the University of Minnesota.

Our laboratory specializes in the design and development of new anti-cancer biologic agents with the goal of getting them into the clinic as quickly as possible. Typically, new hybrid proteins are synthesized by combining genes encoding cancer cell binding domains with genes encoding molecules that deliver death signals. The resulting proteins selectively bind to cancer cells, internalize the death signal, and kill the cancer cells. Thus, they provide cancer specific therapy in a manner that chemotherapeutic agents cannot. These new anti-cancer agents are primarily directed to overexpressed signal markers on the surface of cancer cells and we have successfully produced promising fusion proteins that can kill brain tumors, breast cancer, leukemia, and cells causing organ rejection. In order to facilitate the delivery of these agents at the site of the tumor, another approach under study uses gene therapy. We are fashioning retroviruses containing our target genes and using them to infect tumor reactive T cells. The T cells have the ability to migrate to tumor and secrete the anti-cancer molecule at site where they can have the greatest effect. Another facet of our work focuses on the use of targeting powerful beta irradiation-emitting radionuclides, to cancer cells. Certain isotopes can be conjugated to cancer cell binding antibodies in such a way that they can selectively bind to tumors and cause their regression. In this instance, internalization of these molecules into cells are unnecessary. The cross-fire effect is potent enough to destroy even large tumors and the side effects seem tolerable. Through the design and production of these new molecules we hope to not only devise urgently needed alternative cancer therapies, but to further our understanding of the intricacies of protein engineering.

Clinical Summary

Transplantation, cancer, leukemia, molecular therapeutics, gene therapy

Bio

Dr. Wei is a Distinguished McKnight University Professor, and a Full Professor of the Dept. of Pharmacology. She received B.S. (Botany) from National Taiwan University, M.S. (Microbiology & Immunology) from the University of Michigan, Ph.D. (Microbiology) from Texas Tech Health Sciences Center and post-doctoral training (Microbiology/Medicine) from Columbia University College of Physicians & Surgeons. Dr. Wei joined the Dept. Pharmacology, University of Minnesota, as an Assistant Professor in 1993, was promoted to tenured Associate Professor in 1999, and Full Professor in 2003. She was named Distinguished McKnight University Professor in 2009 till present. Since 1993, Dr. Wei has been continuously supported by multiple research projects by the NIH till today.

Research Summary

Dr. Wei's lab is interested in regulatory pathways and underlying mechanisms in diseases related to motor function, neuro-endocrine regulation, and immunity . Key targets of investigation are: a) 3D-organ culture of neural muscular junction (NMJ) , b) hypothalamus-pituitary regulation/signaling in aging/stress, c) regulation of exosome secretion by vitamin A, and d) hormonal regulation of chromatin remodeling (eipgenetics). Major experimental systems/methods include genetic (CRISPR-edited) mouse models , primary/stem cell cultures , in vitro 3D organ culture of NMJ , and d) molecular, biochemical and biophysical methods for drug screening. The ultimate goal is for developing new therapeutic and diagnostic tools.

Bio

Dr. Wickman is a Professor and Head of the Department of Pharmacology. He received his BA in Chemistry (summa cum laude) from Saint Olaf College in Northfield, MN. Subsequently, he earned his PhD in Molecular Neuroscience (advisor: Dr. David Clapham) from the Mayo Foundation for Biomedical Research in Rochester, MN. Following postdoctoral training at Mayo Clinic Scottsdale (advisor: Dr. Sandra Gendler) and Children's Hospital/Harvard Medical School in Boston, MA (advisor: Dr. David Clapham), he accepted a tenure-track faculty position (Assistant Professor) in Pharmacology at the University of Minnesota in 1999. He was promoted to Associate Professor in 2005, and Professor in 2011. He currently holds the titles of Distinguished University Teaching Professor and Distinguished McKnight University Professor.

Research Summary

Research in the Wickman lab centers on mechanisms controlling the excitability of cells in the heart and brain. Dysregulation of cell excitability contributes to many debilitating and/or life-threatening medical conditions, including cardiac arrhythmias, epilepsy, anxiety, depression, schizophrenia, Down Syndrome, addiction, and pain. The Wickman lab seeks to obtain detailed understanding of molecular mechanisms that regulate cell excitability, so that safer and more effective strategies to treat these medical problems can be envisioned and developed. Investigators in the Wickman lab are currently using approaches in electrophysiology, neuromodulation, genetic manipulation, intracranial pharmacology, cardiac physiology, and behavioral assessments relevant to addiction, anxiety, learning, and pain to understand the physiological and pathophysiological relevance of inhibitory signaling pathways.

Research Summary

Neurotransmission of Pain Dr. Wilcox and colleagues are engaged in research into the spinal neurotransmission of pain and mechanisms underlying hyperalgesia, analgesia and analgesic tolerance. Studies of both excitatory and inhibitory neurotransmission in the rodent spinal cord apply behavioral, electrophysiological (both in vivo and in vitro),immunocytochemical and molecular techniques. Behavioral experiments define biologically relevant interactions, which are then examined at the cellular and molecular level using the more reductionist approaches. A key feature of research projects in this laboratory is open collaboration with laboratories located both here and at other universities. One major thrust of these investigations examines neurotransmitters thought to mediate major components of excitatory neurotransmission from primary afferent sensory fibers to secondary projection neurons in spinal cord dorsal horn: the excitatory amino acids (EAAs) like glutamate and the neurokinins like substance P. Intense or prolonged excitatory transmission via both these pathways is thought to evoke long term synaptic plasticity and excitotoxicity, which may underlie the development of some chronic pain states. A second major focus of work in the laboratory is the characterization of several inhibitory neurotransmitters and their receptors which together modulate this excitation. The neurotransmitters, enkephalin, serotonin and noradrenaline, inhibit various components of the incoming excitatory pain message in the dorsal horn via a number of inhibitory receptor subtypes. We are characterizing the interactions between these receptor subtypes and localizing them using transgenic mice, antisense oligonucleotides and immunocytochemical techniques. Finally, Dr. Wilcox facilitates access for Neuroscience students to high performance computing laboratories on campus - The Laboratory for Computational Science & Engineering and The Minnesota Supercomputer Institute (MSI). High performance computers and visualization are now finding applications in biological imaging, macromolecular modeling and neuronal simulation. A recent neuroscience graduate student developed a new method to optimize correspondence between neuronal simulations and experimental structure-function data.

Research Summary

My lab is interested in understanding the contribution of myeloid cells in the pathogenesis of metabolic and cardiovascular diseases, like atherosclerosis. We aim to determine mechanisms regulating the development and function of tissue-resident macrophages, as well as fate-decisions of circulating monocytes upon entry into inflamed tissues.

Bio

Administrative Contact: Kelli Tourand |  612-624-4581 | toura018@umn.edu

Research Summary

Cancer gene therapy with Adenovirus Vector Conditionally replicative adenovirus for the treatment of cancer Non-invasive in vivo molecular imaging Gene therapy of gastrointestinal diseases, pancreatic cancer, esophageal cancer, prostate cancer, breast cancer, and multiple myeloma Cancer gene-therapy and virotherapy Our goal is to develop clinically usable gene-/viro-therapy modalities for solid tumors, e.g. GI cancers including pancreatic cancer. Our group has been developing cancer therapeutics with adenovirus as gene delivery tool. Current gene therapy modalities for cancer have not achieved the expected therapeutic efficiency due to disease related obstacles. Our lab is developing advanced version of adenovirus vectors and oncolytic adenoviruses by employing virological advance. We perform extensive vector engineering and produce the viruses/vectors to overcome the issues impeding clinical realization of this kind of therapeutics. Recent advances include 1) Development of adenovirus targeting ligand library and its application to the targeted delivery upon systemic administration, 2) Theranostics enables tumor imaging and tumor selective radiotherapy employing sodium-iodine symporter, 3) Combination viro-therapy with INF-alpha expressing oncolytic adenovirus and chemoradiation, 4) Development of cancer stem cell targeted oncolytic adenovirus.

Bio

I am a medical oncologist with a specialty in breast cancer. My laboratory has been interested in the regulation of cancer cells by the insulin-like growth factors (IGFs) and insulin. I also maintain an active clinical practice in the medical management of breast cancer. As part of my clinical care, I also serve as the site principal investigator on several clinical trials that employ experimental therapies targeted against IGF receptor and the PI3K pathway. I am chair in of the Agent Selection Committee of I-SPY2 and I also serve on the Executive Committee of this trial designed to validate investigational therapies in the neoadjuvant treatment of breast cancer. I have been the director of the Masonic Cancer Center since 2007. I have maintained these clinical, translational, and research activities to best identify strategies for improved outcomes in cancer.

Research Summary

Administrator Info
Name: Marina Sladojevic
Phone: 612-626-5475
Email: marinas@umn.edu
Mail: Masonic Cancer Center, University of Minnesota
420 Delaware Street SE
MMC 806
Minneapolis, MN 55455

Summary

My laboratory has been interested in the regulation of cancer cells by insulin and the insulin-like growth factors ( IGFs ). Our laboratory was one of the first to show a role for this pathway in Ewing's sarcoma and breast cancer. The laboratory remains focused on the signaling pathways regulated by the IGFs that are relevant to cancer biology. We have shown that IGF signaling is dependent on activation of specific adaptor proteins and downstream signaling molecules. Our lab is also evaluating the role for the fetal isoform of the insulin receptor (IR-A) in breast cancer biology. Interactions between estrogen receptor expressing breast cancers and insulin/IGFs result in enhanced growth and increased survival. While some anti-IGF strategies have been tested in clinical trials, toxicities and lack of targeting of IR-A has limited the clinical efficacy and the laboratory is working on strategies to target IR-A specifically without inhibition of the adult isoform of insulin receptor (IR-B).

Clinical Summary

Breast cancer