Faculty

Bio

Administrator Info
Name: Drew Keup
Email: keupx013@umn.edu
Mail: 420 Delaware ST SE
MMC 108
Minneapolis, MN 55455

Summary
Dr. Daniel Mueller is a Professor of Medicine, and the Director of Rheumatic and Autoimmune Diseases at the University of Minnesota Medical School. He undertook his medical studies at the University of Wisconsin-Madison School of Medicine, and later obtained his Internal Medicine training at the Ohio State University Hospital. In 1986, he received training in basic molecular immunology in the Laboratory of Immunology at the National Institute for Allergy and Infectious Disease, NIH, under Drs. Ronald Schwartz and William Paul. It is there that he initiated his research into fundamental mechanisms involved in the development and maintenance of immune self-tolerance. In 1990, Dr. Mueller entered the Rheumatology Fellowship Training Program in the Rheumatic Diseases Division/Department of Internal Medicine at the University of Texas Southwestern Medical Center, under Dr. Peter Lipsky. Since the completion of his medical and research training, he has been on the University of Minnesota Medical School faculty. He currently holds the John F. Finn Arthritis Foundation Land Grant Chair. He is also a member of the Autoimmunity Program, within the University's Center for Immunology. The major focus of his academic program is the investigation of the biological and biochemical mechanisms that underlie the induction and maintenance of T- and B-cell tolerance within the peripheral immune system. His goal is the design of curative antigen-specific treatment strategies for autoimmune disease.

Research Summary

• Biological and biochemical nature of immune self-tolerance
• T cell immune tolerance
• T cell clonal expansion
• Breakdown of B cell tolerance during autoimmune disease development
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Current Research Efforts: 

Autoimmunity develops as the consequence of a loss of tolerance to self-antigens. Investigations carried out by Dr. Daniel Mueller are leading to a better understanding of the biological and biochemical nature of immune self-tolerance. Of particular interest are those factors that determine whether prolonged and continuous antigen stimulation of a T cell will lead to an increase in the clone size and the development of protective (or pathological) effector function, or alternatively lead to functional inactivation (anergy) and T regulatory cell (Treg) differentiation. To approach this problem, Mueller's research team is currently using an assortment of genomics and bioinformatics techniques (scRNA-Seq, ATAC-Seq) to characterize gene regulatory patterns in CD4 T cells that are associated with anergy induction and Foxp3+ Treg generation. Candidate gene regulators are being interrogated within neonatal mice--a time at which peripheral tolerance induction is essential for the avoidance of autoimmunity.

Loss of T cell tolerance also allows for the expansion and differentiation of autoreactive B cells, and the development of B-dependent autoimmune disease. Currently, these biological principles are being investigated in models of CD4 T cell-mediated immunopathology using both monoclonal TCR-transgenic T cells as well as self-antigen specific polyclonal responder cells. Additionally, translational experiments continue to detail the repertoire of human autoreactive B cells in normal subjects as well as in patients with Rheumatoid Arthritis. Currently, experiments are exploring the role of Ig gene somatic hypermutation in the generation of arthritogenic B cells by biochemically characterizing the antigen specificity of families of autoreactive B cell antigen receptors all derived from the same B cell progenitor.

Bio

Ryan Nelson is a graduate of the MD/PhD training program at the University of Minnesota. He completed pediatrics residency and Allergy/Immunology fellowship training at Boston Children’s Hospital. As a physician-scientist, he provides care for patients with primary immunodeficiencies, immune dysregulation disorders, and allergic diseases. His research interests focus on CD4+ T cell specificity, functional diversity, trafficking, and memory. He aims to build a translational research program using new approaches to define factors influencing human variability in adaptive immunity to pathogens and maladaptive responses to allergens and self tissues. The goal of this work is to uncover pathways that inform better therapies for patients with immune disorders.

Research Summary

Central Nervous System Penetration by Cryptococcus neoformans Fungal infections affect billions of people every year, often causing lethal disease in immunocompromised individuals. Of particular concern are invasive fungal infections, estimated to kill one and a half million people annually. Cryptococcus neoformans infections cause almost half of all deaths due to fungal infection. Even with access to the best available antifungals, Cn mortality rates of 20-40% remain unacceptably high. Although natural immunity to fungal infection is quite efficient in immune replete humans, disease in immune deficient individuals is often a complex interaction between failure to control fungal replication and an inappropriate immune response. My research program focuses on understanding how Cryptococcus causes disease, with the goal of developing better treatment strategies that improve patient survival. Our research primarily focuses on studies to understand the novel "titan cell" morphology during Cryptococcus infection. Upon inhalation, Cryptococcus establishes an initial pulmonary infection that eventually disseminates to the central nervous system (CNS) to cause meningitis. In response to the host pulmonary environment, a subset of Cryptococcus cells become titan cells that are 5-10x larger than typical-sized cells. These titan cells are critical for virulence, impact dissemination to the CNS, and their production during the infection dramatically alters the host response by reducing phagocytosis and stimulating a detrimental Th2-mediated response. Our current research is aimed at understanding the molecular mechanisms and host-pathogen interactions underlying the activity of titan cells during infection.

Research Summary

Dr. Orr is professor and the James Schindler and Bob Allison Ataxia Chair in Translational Research in the department, directs the Institute of Translational Neuroscience, and is a member of the Division of Molecular Pathology and Genomics.  His research is focused on the molecular genetics of neurodegenerative diseases, principally the autosomal dominant form of spinocerebellar ataxia (SCA1). Patients usually develop SCA1 in mid-life. They experience loss of motor coordination and develop slurred speech, spasticity, and cognitive impairment. These symptoms arise from the loss of Purkinje cells and damage to other nerve cells in the brain's cerebellar cortex. Orr and his colleagues cloned the SCA1 gene and found that the disease is caused by the expansion of an unstable, repeated cytosine-adenine-guanine (CAG) sequence in DNA. The length of the trinucleotide repeat is associated with when symptoms develop.The trinucleotide repeat encodes an expanded polyglutamine tract, an important step in disease pathogenesis. Orr and his colleagues established the first transgenic mouse model for SCA1 with which they were able to induce ataxia with Purkinje cell features characteristic of SCA1 by inserting CAG repeats. The model has helped his team understand how the SCA1 mutant polyglutamine protein, ataxin-1, moves from the cytoplasm into the nucleus of Purkinje cells where together with other protein complexes it causes Purkinje dendrites to atrophy. They found that phosphorylation of a specific ataxin-1 serine results in greater stabilization of the mutant protein, which alters the normal ratio of stabilized versus degraded protein and results in aberrant binding and disease.In the experimental therapeutics arena, Orr and colleagues are using RNA interference (RNAi) and adeno-associated virus (AAV) vectors as a delivery system to reduce ataxin-1 expression in Purkinje cells. Orr also working with a company that has developed anti-sense oligonucleotide chemistry. Anti-sense oligonucleotides act at the level of messenger RNA before proteins are produced. Delivering drugs to the central nervous system is difficult. Delivering molecular therapies to the deep cerebellar nuclei of the cerebellar cortex, where Purkinje neurons cluster and terminate, is a significant challenge. Orr's University colleagues have experience using AAV vectors to deliver genes to Purkinje cells. When human trials begin, the hope is that a sufficient number of therapeutic molecules will be taken in by Purkinje cell terminals and transferred to the cell bodies to be beneficial to patients.

Publications

• Liu CJ, Williams KE, Orr HT, Akkin T. Visualizing and mapping the cerebellum with serial optical coherence scanner. Neurophotonics. 2017 Jan;4(1):011006.
• Rubinsztein DC, Orr HT. Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. Bioessays. 2016 Oct;38(10):977-80. doi: 10.1002/bies.201600048.
• Ingram M, Wozniak EA, Duvick L, Yang R, Bergmann P, Carson R, O'Callaghan B, Zoghbi HY, Henzler C, Orr HT. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron. 2016 Mar 16;89(6):1194-207. doi: 10.1016/j.neuron.2016.02.011.
• Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, Nelson RW, Fife BT, Orr HT, Anderson MS, Hogquist KA, Jenkins MK.
  Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns.
  Nat Immunol. 2016 Feb;17(2):187-95. doi: 10.1038/ni.3327.

Bio

Angela Panoskaltsis-Mortari, PhD is a Professor of Pediatrics in the Division of Blood and Marrow Transplant & Cellular Therapy. She is also a Professor of Medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep. Dr. Panoskaltsis-Mortari is the Director of the Cytokine Reference Laboratory, the Director of the 3D Bioprinting Facility at the University of Minnesota and Vice Chair for Research for the Department of Pediatrics.
Dr. Panoskaltsis-Mortari received her PhD from the University of Western Ontario. She was a post-doctoral fellow in the Department of Pathology at the University of Alabama and a post-doctoral research associate in the Department of Pediatrics at the University of Minnesota. She joined the University of Minnesota faculty in 1995.
Dr. Panoskaltsis-Mortari has board certification from the American Board of Medical Laboratory Immunology. She is a member of numerous immunology, pulmonary, and hematology professional societies, and the author of over 275 articles which have appeared in such publications as Advanced Materials, Journal of Clinical Investigation, Blood, Biology of Blood and Marrow Transplantation, and American Journal of Physiology (Lung, Cell. & Mol. Physiol.).

Research Summary

With 25 years of experience in animal models of stem cell transplant, lung injury, mesenchymal stem/stromal cell therapy and the biology of graft-vs-host disease (GVHD) after bone marrow transplant, Dr. Angela Panoskaltsis-Mortari's work has evolved into the bioengineering field, and she is recognized as one of the thought leaders in lung bioengineering. Dr. Panoskaltsis-Mortari's laboratory research currently focuses upon 2 major themes: 1) bioengineering autologous tissues such as trachea and esophagus using 3D bioprinting and customized hydrogels including decellularized extracellular matrix; and 2) 3D bioprinting of cancer models.
Dr. Panoskaltsis-Mortari established and directs the 3D Bioprinting Facility at the University of Minnesota. She also directs the UMN Cytokine Reference Laboratory (a CLIA-licensed facility). She is a member of the Stem Cell Institute, the Institute for Engineering in Medicine, the Lillehei Heart Institute, the Masonic Cancer Center, the Center for Immunology, and the Robotics Institute. She is funded by the NIH, has mentored many post-docs, MD trainees, graduate students and undergrads in various training programs. Her goal is to realize the potential of regenerative medicine by converging the fields of stem cell biology, mechanical & biomedical engineering, biomaterials, physiology, robotics, and surgery to bioengineer autologous tissues/organs for transplant using a patient's own cells that would not be rejected by their immune system.

Bio

If you would like to schedule an appointment with Dr. Pearson, please call: (612) 625-5656.

I strive to provide individualized, evidence-based care for all of my patients.

Research Summary

Autoimmune connective tissue disease, autoimmune bullous disease

Clinical Summary

Clinics:
Dermatology Clinic

Board Certifications:
Dermatology

Clinical Interests:
Dermatomyositis, cutaneous lupus, systemic sclerosis, pemphigoid, pemphigus, severe cutaneous drug reactions, morphea
 

Research Summary

Dr. Pennell's laboratory is investigating novel strategies for immunotherapy, drawing on the immune system's inherent specificity as part of a personalized medicine approach for treating cancer. His team is using the tools of immunology, molecular biology, genetic engineering, and transgenic animals in two research areas that have potentially synergistic applications: the development of DNA-based cancer vaccines; and the development of T-cell chimeric antigen receptors engineered to recognize and bind specific tumor cell-surface antigens, activating T-cell cytotoxicity.Pennell's team developed DNA-based vaccines designed to increase antigen expression on tumor cells, which in turn enables CD8 T-cells to recognize and bind to these tumor cells, activating T-cell cytotoxicity. Initially they used plasmid DNA as a delivery vehicle. Because few cells tend to take up the new DNA plus the fact that expression of the DNA-encoded protein is transient, the therapeutic effects register at a very low level. Recently they turned to using smaller DNA minicircle constructs as delivery vehicles, with notable success. Minicircle DNA confers higher levels of sustained transgenic expression than plasmid DNA upon delivery in an infectious disease model in mice. Pennell and fellow University faculty are now adapting minicircle DNA delivery for cancer vaccine immunotherapy in a mouse model with the long-term goal of developing minicircle-based DNA vaccines to treat human cancer.Pennell's team is coupling its research on DNA vaccines with that in a related field called T-cell chimeric antigen receptors (CARs). Like DNA vaccines, CAR technology is also based on co-opting a patient's own immune system specificity. CARs are genetically engineered receptors introduced into white blood cells, specifically T cells. CARs override the native specificity of the T cell and cause the T cell to become activated when the CAR specifically binds an antigen. An antibody-derived fragment displayed on the outside of the T cell confers CAR specificity; the inside of the CAR receptor contains T cell-derived proteins required for activation. The antibody effects a higher affinity binding than the usual T-cell receptor–major histocompatibility complex (MHC) molecule binding. T cells modified to express antibody-based CARs circumvent MHC restriction and potently kill tumor cells bearing the antigen for which the CAR is specific.CAR-based therapy has shown dramatic success in adoptive immunotherapy trials of patients with acute lymphocytic leukemia (ALL) who are refractory to standard chemotherapy. Pennell's laboratory is developing CAR mouse models to address the side effects of CAR immunotherapy in ALL. The side effects include the depletion of healthy B-cells as well as tumor B-cells, making the patients B-cell aplastic, and the potential massive release of pro-inflammatory cytokines. Pennell and his University colleagues (notably Drs. Bruce Blazar and Mark Osborn in the Department of Pediatrics) are using clinically tested mouse T-cell CARs with human components that recognize the human antibody CD19, which they have engineered to be expressed in mice B-cell tumors. Their goal is to determine the right dose-based balance between achieving anti-tumor effects and avoiding potentially harmful side effects of CAR therapy.

Publications

• Pennell CA, Campbell H, Storlie MD, Bolivar-Wagers S, Osborn MJ, Refaeli Y, Jensen M, Viaud S, Young TS, Blazar BR. Human CD19-specific switchable CAR T-cells are efficacious as constitutively active CAR T-cells but cause less morbidity in a mouse model of human CD19⁺ malignancy. J Immunother Cancer. 2022 Dec;10(12):e005934. doi: 10.1136/jitc-2022-005934
• Bolivar-Wagers S, Loschi ML, Jin S, Thangavelu G, Larson JH, McDonald-Hyman CS, Aguilar EG, Saha A, Koehn BH, Hefazi M, Osborn MJ, Jensen MC, Wagner JE, Pennell CA, Blazar BR. Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses. JCI Insight. 2022 Sep 8;7(17):e160674. doi: 10.1172/jci.insight.160674.
• Christopher A. Pennell, Jessie L Barnum, Cameron McDonald-Hyman, Angela Panoskaltsis-Mortari, Megan J. Riddle, Zhengming Xiong, Michael Loschi, Govindarajan Thangavelu, Heather M. Campbell, Meghan D Storlie, Yosef Refaeli, Scott N Furlan, Michael C. Jensen, Leslie S Kean, Jeffrey Scott Miller, Jakub Tolar, Mark Osborn, Bruce R Blazar. Human CD19-targeted mouse T cells induce B cell plasia and toxicity in human CD19 transgenic mice. Molecular Therapy, 2018; doi: 10.1016/j.ymthe.2018.04.006 [Epub ahead of print]
• Andersen BM, Xia J, Epstein AL, Ohlfest JR, Chen W, Blazar BR, Pennell CA, Olin MR.  Monomeric annexin A2 is an oxygen-regulated toll-like receptor 2 ligand and adjuvant.  J Immunother Cancer. 2016 Feb 16;4:11. doi: 10.1186/s40425-016-0112-6.
• Pluhar GE, Pennell CA, Olin MR. CD8? T Cell-Independent Immune-Mediated Mechanisms of Anti-Tumor Activity. Crit Rev Immunol. 2015;35(2):153-72.

Bio

Administrator Info
Name: Drew Keup
Email: keupx013@umn.edu
Lab Phone: 612-626-6100
Mail: 420 Delaware ST SE
MMC 108
Minneapolis, MN 55455

Summary
Dr. Erik Peterson joined the division of Rheumatic and Autoimmune Diseases in July, 2002. He is a member of the interdisciplinary Center for Immunology and its Autoimmunity Program, as well as a member of the Cancer Center. He is an immunologist with a scientific interest in those molecules that regulate the development and function of the immune system and prevent or promote the development of autoimmunity. He is also practices general rheumatology and participates in Resident and Fellow teaching.

Research Summary

Research in the Peterson laboratory

Dr. Erik Peterson has strong interests in the molecular underpinnings of autoimmune diseases, including rheumatoid arthritis, lupus, and myositis. His laboratory utilizes genetic, biochemical, and primary human sample-based approaches to investigating the mechanisms whereby recently identified “risk” genes predispose to development of autoimmune disease. Dr. Peterson's group recently identified a role for Ptpn22, a potent “risk” gene for many autoimmune diseases, in the promotion of toll-like receptor signaling and type 1 interferon production. He is currently investigating the role of Ptpn22 in myeloid cell functions in systemic lupus and in responses to immunization, and is characterizing the molecular mechanism of Ptpn22 promotion of type 1 interferon signals.

Leukocyte activation and development

Investigations carried out in Dr. Erik Peterson’s laboratory aim to increase understanding of the molecular mechanisms behind newly identified risk genes associated with autoimmune diseases. The laboratory uses human peripheral blood, genetically-altered mice, and transformed cell lines to approach questions concerning the biochemical, cellular, and immune response-modulating functions of susceptibility alleles.

The PTPN22 gene is among the strongest genetic predisposition factors for major human autoimmune diseases, including type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). PTPN22 encodes lymphoid tyrosine phosphatase (Lyp); a Lyp variant bearing a R620W substitution (“LypW”) is causally associated with disease risk. Lyp is a well-known negative regulator of T cell receptor (TCR) signaling, and most functional genomic work to date has focused on the potential mechanisms of LypW variant action on adaptive immune processes. Despite intensive study, a comprehensive model for LypW mechanism(s) of action in autoimmune disease is lacking.

In collaboration with others at UMN and elsewhere, our group recently demonstrated that PTPN22 plays a critical positive role in regulating pattern recognition receptor (PRR) signaling leading to production of type 1 Interferons (IFN) by myeloid cells. We established that Lyp protein binds and promotes activation of TNF Receptor Associated Factor 3 (TRAF3) during myeloid cell PRR signaling. Lyp also promotes PRR-induced, type 1 IFN-driven anti-viral host defense and suppression of inflammation in the gut and in the joint lining synovium. Importantly, the LypW variant exhibits reduced-function behavior in PRR signaling and in type 1 IFN-governed suppression of inflammation.

Our observations that PTPN22 modulates myeloid cell signaling suggest new potential mechanisms whereby an autoimmunity-associated gene works in concert with suspected environmental stimuli (e.g. viral infections, inflammatory reactions) to result in tissue damage. Our working model holds that PTPN22 potentiates myeloid cell-directed type 1 IFN-dependent anti-microbial host defense andcounter-inflammatory mechanisms. The model also holds that the reduced function LypW variant enhances potential for autoimmunity by increasing host susceptibility to tissue damage by suboptimally-suppressed infections and/or inflammatory reactions. Major questions about the model remain:

1. Is myeloid cell-intrinsic Lyp function sufficient for major host defense and anti-inflammatory PTPN22 actions in vivo?
2. What is the molecular basis for Lyp promotion of TRAF3 signaling?
3. How does LypW function differently in myeloid cell signaling and type 1 IFN-driven processes in vivo?
4. How do Lyp functions in host-defense and inflammation suppression translate into autoimmune disease risk

By experimentally addressing questions such as these, we seek to identify novel therapeutic targets, high-quality biomarkers, and ultimately, the cure for systemic rheumatic diseases.

Clinical Summary

Rheumatoid arthritis; Psoriatic arthritis; Systemic lupus erythematosus

Bio

Dr. Revelo is an Associate Professor in the Department of Integrative Biology & Physiology and Center for Immunology. He has a broad background in physiology, immunology, and metabolism and expertise in inflammation during cardio-metabolic disease. His research explores the role of the immune system and inflammation in the pathophysiology of obesity-related diseases such as fatty liver disease and heart failure.

Research Summary

Dr. Revelo's research program focuses on the following areas:
1. Mechanisms of hepatic and intestinal inflammation in fatty liver disease and cancer.
2. Immune mechanisms of cardiac remodeling during heart failure
3. Anti-inflammatory mechanisms of exercise training and bariatric surgery

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
Name: Craig Olson
Phone: 612-626-6577
Email: olso7966@umn.edu
Mail: 420 Delaware ST SE
MMC 250
Campus Delivery Code 8250A
Minneapolis, MN 55455

Summary
Timothy Schacker, M.D. is a professor of Medicine and Director of the Program in HIV Medicine at the University of Minnesota. He joined the faculty in 1996. Dr. Schacker received his M.D. from the University of Minnesota in 1986 and completed a residency in Internal Medicine at the Oregon Health Sciences University and Infectious Disease Fellowship at the University of Washington in 1993. He then joined the faculty of the University of Minnesota.Dr. Schacker is interested in how HIV causes immune suppression and why antiretrovirals do not fully restore immunity. His group focuses on inflammatory damage in lymphatic tissues; the principal site of HIV infection, that results in fibrosis of the lymphatic structures required to maintain a normal population of CD4 cells. They are testing novel therapies to prevent and/or reverse this process and slow T cell depletion in HIV and improve their reconstitution when antiretroviral is begun. He is also the principal investigator of a federally funded program of projects designed to determine barriers to HIV eradication. In addition, Dr. Schacker has established a collaboration with the Joint Clinical Research Center in Kampala, Uganda to study how constant exposure to common infections like tuberculosis, malaria, and helminthic infections affect rates of HIV transmission and progression.

Research Summary

IL-15 to Deplete HIV Reservoirs and Improve Immune Responses; Antifibrotic Therapy to Improve Immune Reconstitution in HIV

Research Funding Grants

• Predictors of Time to Viremia with an Analytic Treatment Interruption, amfAR, 109496-60-RGRL, Principal Investigator.
• Reservoir Dynamics in Patients Treated in Very Early Acute HIV Infection, NIH, R01 AI125127, Principal Investigator.
• Reversing Tissue Fibrosis to Improve Immune Reconstruction in HIV, NIH, U01AI105872, Principal Investigator.
• Antifibrotic Therapy to Improve Immune Reconstitution in HIV, NIH, R01 AI093319-01A1, Principal Investigator.
• IL-15 to Deplete HIV Reservoirs and Improve Immune Responses, Altor Bioscience, ALT-803, Principal Investigator.

Clinical Summary

HIV

Bio

Mark R. Schleiss, MD, is a Professor of Pediatrics in the University of Minnesota Medical School. Dr. Schleiss received his MD degree from the Oregon Health and Sciences University, Portland, Oregon. He completed his residency at Doernbecher Children's Hospital, Oregon Health and Sciences University, Portland, Oregon, and his Pediatric Infectious Diseases fellowship at Seattle Children's Hospital/Medical Center, University of Washington, Seattle, Washington. He also completed a fellowship in Molecular Medicine studying cytomegalovirus (CMV) molecular genetics at the Fred Hutchinson Cancer Research Center, Seattle, Washington.

His work in basic, translational and clinical research related to CMV infection is described at cmv.umn.edu

Clinical Summary

Pediatric Infectious Diseases; Vaccines; Vaccine Advocacy; Antimicrobials and Antivirals; Clinical Virology; Maternal-Fetal Infections

Bio

Nathan Schuldt, PhD, is an Assistant Professor in the Department of Pediatrics in the Division of Pediatric Rheumatology. Dr. Schuldt runs a laboratory at the University of Minnesota's Center for Immunology. His laboratory investigates the origins of autoimmune diseases like type 1 diabetes (T1D) and multiple sclerosis (MS). Dr. Schuldt has particular interest in T cell development, tolerance, and fate decisions.

Dr. Schuldt earned his PhD in Genetics in 2012 at Michigan State University training in the laboratory of Andrea Amalfitano, DO, PhD. His graduate studies focused on the interactions between adenovirus and the immune system with the goal of improving adenovirus-based vectors for gene therapy and vaccination. He joined the University of Minnesota Center for Immunology in 2012 as a Postdoctoral Fellow.

Research Summary

Multiple immune tolerance mechanisms prevent self-reactive T cells from becoming pathogenic. Autoimmunity occurs when these mechanisms break down. Thymic selection, also referred to as central tolerance, is the first prevention a self-reactive T cell encounters. During this process antigen recognizing T cell receptors (TCRs) are tested against various self-peptides, those that react too strongly are either deleted or shuttled into the regulatory T cell lineage. My research aims to understand how self-reactive T cells escape this process and initiate autoimmune disease.

One hypothesized method is through the expression of two different TCRs on a single T cells. An estimated 10-20% of all T cells express two functionally recombined TCRs. We hypothesize that this dual TCR expression can limit deletion and regulatory T cell commitment of strongly self-reactive T cells in the thymus. This could explain how self-reactive T cells escape the thymus and enter the periphery as pathogenic T cells. Dual TCR expression is hypothesized to play important roles in several other immune contexts including allo-responses in graft rejection, allergy, and protective immunity. We have developed new tools in our lab that allow us to detect and study dual TCR T cells in several immune contexts.

A second area of interest for the lab is neonatal immune development. At birth, the adaptive immune system is underdeveloped and may function differently than that of adults. As a result, infections are common in neonates and infants. The Schuldt Lab has begun a collaboration to investigate how early microbial exposure influences the development of adaptive immunity. Improved understanding of neonatal adaptive immunity could lead to improved vaccine platforms.

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 focus 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 carry 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 aimed at determining 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

• Bapat AS, O'Connor CH, Schwertfeger KL. Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors. Sci Rep. 2023 Apr 1;13(1):5349. doi: 10.1038/s41598-023-32321-0
• Tarullo SE, He Y, Daughters C, Knutson TP, Henzler CM, Price MA, Shanley R, Witschen P, Tolg C, Kaspar RE, Hallstrom C, Gittsovich L, Sulciner ML, Zhang X, Forster CL, Lange CA, Shats O, Desler M, Cowan KH, Yee D, Schwertfeger KL, Turley EA, McCarthy JB, and Nelson AC.  Receptor for hyaluronan-mediated motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients. The Journal of Pathology. First published: 26 April 2023  https://doi.org/10.1002/path.6082.  Note: This research was supported in part by the LMP initiative in spatial 'omics. 
• Witschen PM, Chaffee TS, Brady NJ, Huggins DN, Knutson TP, LaRue RS, Munro SA, Tiegs L, McCarthy JB, Nelson AC, Schwertfeger KL. Tumor cell-associated hyaluronan-CD44 signaling promotes pro-tumor inflammation in breast cancer. Cancers 2020, 12, 1325. https://doi.org/10.3390/cancers12051325. 
• 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

My research program investigates the intersections between the worlds of perinatal biology and cellular immunology to identify and understand underlying mechanisms that contribute to the development of maternal diseases. My work currently focuses on identifying and developing novel, personalized cellular immunotherapy approaches to treat and prevent hypertensive diseases in pregnancy. Other work in the lab focuses on the impact of maternal diseases on the future health of mom. The development of safe, novel therapeutic interventions for maternal diseases are vital to improving women's health in both the short-term and the long-term.

Further, as an under-represented minority and a first-generation college graduate, teaching and inspiring others to go into science is a priority in my personal and professional lives. I have had exceptional mentors throughout my training. These mentors and the acceptance of my own personal journey has inspired me to seek opportunities to mentor other diverse learners throughout my career. I strive to provide the same high level of mentorship that I have received to those I train to ultimately provide a more inclusive and equitable representation in science and medicine.
 

Publications

Bio

Dr. Shimizu is focused on trying to understand how immune responses are generated and how that information can be used in the clinic to improve patient care. He and his colleagues are particularly interested in identifying the general principles by which the T-cell response is initiated. These cells require contact with other cells order to become activated and play their role in an antigen-specific immune response. Cellular adhesion processes and cell-surface receptors transmit biochemical signals inside the cells that lead to T-cell activation and differentiation into cytotoxic T cells or helper T cells. Cellular adhesion spurs efficient trafficking of lymphocytes through the body and their influx to inflammatory sites. Shimizu's laboratory is investigating the signaling pathways that regulate the strength of these adhesive interactions. His team is also exploring the functional significance of these T-cell molecular mechanisms and their role in the ability of the immune system to respond to pathogens and tumors.

Research Summary

Shimizu has a long-standing and continuing research interest in the role of integrins in T-cell adhesion and activation. The integrins are a superfamily of cell adhesion receptors that T-cells use to carry out many of their normal functions, including their ability to migrate to sites in the body where they are needed. Shimizu and his University colleagues have identified novel signaling intermediates that promote integrin function and T-cell activation, and are currently investigating the role of integrins in controlling the localization of T-cells to specific anatomic sites in the body. Of particular interest is the tumor microenvironment, which is normally immunosuppressive and thus dampens the ability of T-cells to recognize and kill tumor cells. Sophisticated imaging technologies such as two-photon microscopy now make it possible to track the movement and behavior of T-cells in the normal and tumor tissue microenvironments. Currently, Shimizu and colleagues are using this technology to analyze the behavior of cytotoxic T-cells in the tumor microenvironment and the role of integrins and immune checkpoint blockade in controlling T-cell movement and retention in the tumor microenvironment. Signal transduction, lymphocyte activation, cell adhesion and migration The generation of an antigen-specific immune response requires the coordinated interaction of the various cellular constituents of the immune system with each other and with components of the extracellular environment found in tissue. These adhesive events are critical to the efficient trafficking of lymphocytes through the body, the interaction of T lymphocytes with antigen-presenting cells that initiates and sustains T cell activation, and the influx of leukocytes into sites of inflammation. Dr. Shimizu's laboratory is investigating the intracellular signal transduction events that regulate the strength of these adhesive interactions and the functional significance of these molecular mechanisms of cell adhesion and migration on the ability of the immune system to respond to pathogens and tumors. Specific areas of investigation projects include:  Analysis of the biochemical signaling events by which the antigen-specific T cell receptor regulates the functional activity of integrins, a family of cell adhesion receptors that mediates the adhesion of cells to other cells and to extracellular matrix molecules Mechanisms of receptor "cross-talk" that regulate integrin function The function of adapter proteins in regulating T cell gene transcription and cytoskeletal reorganization Elucidation of pathways mediating the migration and retention of tumor-specific T cells into sites of tumor growth Analysis of the function of the lipid kinase p110gamma in regulating the inflammatory response and T cell-dependent immune responses to vaccinia virus.  Dr. Shimizu's laboratory combines molecular and biochemical approaches with genetic models in the mouse where the impact of altering signaling pathways on the generation of antigen-specific and tumor-specific immune responses can be assessed. The long-term objective is to provide the knowledge base necessary to specifically modulate the immune response by targeting these mechanisms of cell adhesion and migration.

Publications

• Domae, E., Hirai, Y., Ikeo, T., Goda, S., and Shimizu, Y.: Cytokine-mediated activation of human ex vivo-expanded Vg9Vd2 T cells. Oncotarget 2017; 8:45928-45942.
• Banek, C.T., Kneupfer, M.M., Foss, J.D., Fiege, J.K., Asirvatham-Jeyaraj, N., Van Helden, D., Shimizu, Y., and Osborn, J.W. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension 2016; 68:1415-1423.
• Asirvatham-Jeyaraj, N., Fiege, J.K., Han, R., Foss, J., Banek, C.T., Burbach, B.J., Razzoli, M., Bartolomucci, A., Shimizu, Y., Panoskaltsis-Mortari, A., and Osborn, J.W.: Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension 2016; 68:929-936.
• Wang, H., Kwak, D., Fassett, J., Hou, L., Xu, X., Burbach, B., Thenappan, T., Xu, Y., Ge, J., Shimizu, Y., Bache, R., and Chen, Y.: CD28/B7 deficiency attenuates systolic overload-induced congestive heart failure, myocardial and pulmonary inflammation, and activated T-cell accumulation in the heart and lungs. Hypertension 2016; 68:688-696.
• Fiege, J.K., Beura, L.K. and Shimizu, Y.: Adhesion and degranulation promoting adapter protein (ADAP) promotes CD8 T cell differentiation and resident memory formation and function during an acute infection. J. Immunol. 2016; 197: 2079-2089.
• Mitchell, J.S., Burbach, B.J., Srivastava, R., Fife, B.T. and Shimizu, Y.: Multi-stage T cell-dendritic cell interactions control optimal CD4 T cell activation through the ADAP-SKAP55 signaling module. J. Immunol. 2013; 191:2372-2383. PMCID: PMC3772631.
• Zumwalde, N.A., Domae, E., Mescher, M.F. and Shimizu, Y.: ICAM-1 dependent homotypic aggregates regulate CD8 T cell effector function and differentiation during T cell activation. J. Immunol. 2013; 191:3681-3693. PMCID: PMC3803108.
• Srivastava, R., Burbach, B.J., Mitchell, J.S., Pagan, A.J. and Shimizu, Y.: ADAP regulates cell cycle progression of T cells via control of cyclin E and cdk2 expression through distinct CARMA1-dependent signaling pathways. Mol. Cell. Biol. 2012; 32:1908-1917. PMCID: PMC3347422.

Bio

Dr. Sloan is an Assistant Professor, Medical Student Director and Co-lead of the Department Diversity, Equity and Inclusion Committee  in the Department of Radiation Oncology at the University of Minnesota, and is a Masonic Scholar with the Masonic Cancer Center. Her clinical practice specializes in the treatment of tumors of the brain (primary brain tumors and brain metastases) with radiotherapy.

Dr. Sloan completed her undergraduate studies at the University of Pennsylvania. After completing the MD/PhD Program at The Lewis Katz School of Medicine at Temple University and her residency in Radiation Oncology at the Johns Hopkins University School of Medicine, where she was mentored by Dr. Lawrence Kleinberg, Dr. Sudipto Ganguly, and Dr. Drew Pardoll, Dr. Sloan was recruited to the University of Minnesota’s Department of Radiation Oncology in 2020. In 2021, she was appointed the co-lead of the Department of Radiation Oncology Diversity, Equity and Inclusion Committee, and in 2023, she was appointed as the Medical Student Director for the Department of Radiation Oncology. Also in 2023, she became an Executive Committee Member of the Brain Tumor Program at the University of Minnesota. Dr. Sloan became a member of both the NRG Oncology Brain Tumor General Committee and the NRG Oncology Radiation Oncology Committee in 2024.

Dr. Sloan’s primary area of research is the systemic effect of cancer therapy. As a physician-scientist, she leads a translational research laboratory within the University of Minnesota Brain Tumor Program (UMBTP), focused on understanding the role of myeloid cells in primary brain tumors. Dr. Sloan is particularly interested in the impact of radiotherapy on deleterious peripheral blood myeloid cell populations in patients with brain tumors. The overall goal of her translational science program is to personalize radiation therapy based on systemic immune biomarkers. Dr. Sloan is the Principal Investigator (PI) of multiple interventional and observational clinical trials.

Clinical Summary

Radiation oncology; Brain tumors; Brain metastases

Bio

Administrator Info
Name: Drew Keup
Email: keupx013@umn.edu
Mail: 3-240 WMBB
2101 6th St SE
Minneapolis MN 55414

Summary
Dr. Spanier received his BS degree in Cell Biology ('03) and MS degree in Biology ('06) from the University of Minnesota Duluth. While in Duluth Dr. Spanier's research was focused on nutrient transporters in endothelial cells within the blood-brain barrier. Dr. Spanier then moved to the University of Wisconsin Madison where he received a PhD in Biochemistry in 2012. It was in Madison that Dr. Spanier developed his skills in immunology and a passion for understanding autoimmune disease, where his research focused on how vitamin D influences the immune system in context of Multiple Sclerosis. In 2013 Dr. Spanier joined the laboratory of Dr. Brian Fife at the University of Minnesota Center for Immunology. It was here that he began building molecular tools, called peptide: MHCII tetramers, to understand antigen-specific responses in both people and mice with autoimmune diabetes. Dr. Spanier's current research program is focused on understanding autoimmune CD4 T cell responses in type 1 diabetes, and the engineering of monoclonal antibodies and chimeric antigen receptors for the restoration of immune tolerance.

Research Summary

• Clinical Immunology
• Autoimmune Diabetes
• peptide:MHCII tetramers
• vitamin D
• monoclonal antibodies
• Chimeric Antigen Receptors

Teaching Summary

Biochemical Methods Seminar; Topics in Medical Biochemistry ; Advanced Molecular Biology Laboratory; Developmental Biology Laboratory; General Biology Laboratory

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

Dr. Subramanian completed his postdoctoral fellowship at Stanford University and joined the faculty at the University of Minnesota in 2007. Dr. Subramanian has established an internationally recognized cancer research program focused on deciphering the molecular mechanisms of immune evasion in cancer. His current research focuses on understanding how cancer cells and gut microbiome manipulate the anti-tumor immune response in colorectal cancer. Specifically, Dr. Subramanian's research has shed light on how cancer cells and the gut microbiome collaborate to suppress the immune response in patients with colorectal cancer. Dr. Subramanian and his team have revealed a previously unknown mechanism affecting T cell costimulation in colorectal cancer by identifying the immune suppression mediated by cancer- secreted exosomes. These findings have immense clinical relevance, offering new insights into treating advanced-stage colorectal cancer.

Dr. Subramanian's extensive publication record, including over 120 peer-reviewed articles, attests to his high-quality research and impact. He serves as the section Editor-in-Chief of the journal Vaccines and the Associate section Editor-in-Chief of Cancers. As a co-founder and Chief Scientific Officer of EV Therapeutics Inc., Dr. Subramanian is at the forefront of developing clinical-grade engineered exosomes to treat advanced-stage colorectal cancer patients. Moreover, as a leader in his field, Dr. Subramanian is dedicated to training the next generation of scientists and making a difference in people's lives. Beyond his research and teaching, Dr. Subramanian is committed to giving back to his community, a testament to his dedication to scientific advancement and social responsibility.

ACADEMIC APPOINTMENTS: 

• Professor, Department of Surgery
• Member, Masonic Cancer Center
• Member, Center for Immunology
• Senior Graduate faculty, Microbiology, Immunology and Cancer Biology (MICaB) Ph.D. Graduate Program
• Senior Graduate faculty, Molecular Pharmacology and Therapeutics (MPaT) Ph.D. Graduate Program
• Senior Graduate faculty, Bioinformatics and Computational Biology (BICB) Ph.D. Graduate Program 
• Director, Resident Research Enrichment Program, Department of Surgery
• Co-leader, Gastrointestinal Cancer Translational Working Group, Masonic Cancer Center 
• Faculty Director and Mentor, Proposal Preparation Program, Medical School

PUBLICATIONS

Pubmed link

Recent publications:

1. Zhao X, Yuan C, Wangmo D, Subramanian S. Tumor-secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor-specific T-cell responses. Gastroenterology 2021 161: 560-574
2. Wangmo D, Premsrirut PK, Yuan C, Morris WS, Zhao X and Subramanian S. Loss of ACKR4 in tumor cells dysregulates dendritic cell migration to tumor-draining lymph nodes and T-cell priming. Cancers 2021. 7;13(19):5021.
3. Nair, AA Tang X, Thompson KJ, Kalari KR, Subramanian S. MicroRNA response elements frequency identifies dysregulation of MAPK signaling in triple-negative breast cancer. Doi: http://dx.doi.org/10.1101/817098. iScience 2020 23(6):101249
4. Yuan C, Graham M, Subramanian S. Mucosal Microbiota and Metabolome along the Intestinal Tract Reveal a Location-Specific Relationship. mSystems 2020 5(3):e00055-20 5. Zhao X, Kassaye B, Wangmo D, Lou E, Subramanian S. Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors. iScience 2020 23(5):101056

Bio

Jakub Tolar, MD, PhD is the dean of the University of Minnesota Medical School and a Distinguished McKnight University Professor in the Department of Pediatrics, Blood and Marrow Transplant & Cellular Therapy. He is also the vice president for Clinical Affairs at the University of Minnesota, board chair for University of Minnesota Physicians and co-leader of M Health Fairview, the joint clinical enterprise among the University of Minnesota Medical School, University of Minnesota Physicians and Fairview Health Services. An internationally recognized physician and researcher, Dr. Tolar is known for his care of patients with recessive dystrophic epidermolysis bullosa. His research is focused on developing cellular therapies for rare genetic disorders. Originally from the Czech Republic, Dr. Tolar received his medical education (MD) in Prague at Charles University. In 1992, he came to the University of Minnesota, where he received his PhD in Molecular, Cellular & Developmental Biology and Genetics.

Research Summary

Dr. Tolar's research focuses on finding new ways to treat children with lethal, inherited diseases. He is also looking for safer and more effective gene therapy for diseases such as epidermolysis bullosa, mucopolysaccharidosis type I (Hurler syndrome), Fanconi anemia, and dyskeratosis congenita. Additional research interests include reducing the negative effects of stem cell transplantation (such as using mesenchymal stromal cells for graft-versus-host disease); creation and use of induced pluripotent stem cells; gene therapy using gene addition (with viral vectors and trasposons); and gene editing (with synthetic nucleases to repair genes).

Clinical Summary

Blood and marrow transplantation; Gene therapy for correction of genetic diseases

Bio

Administrator Info
Name: Kris Blomquist
Email: krblomqu@umn.edu

Summary
Dr. Tracy graduated from the combined MD/PhD program at Tufts University, receiving his PhD in Immunology. His graduate research focused on the basic biology of the Epstein-Barr Virus. He subsequently completed his residency in Internal Medicine at the Mayo Clinic. During residency, he studied clinical outcomes of patients with lymphoma. He then enrolled in the fellowship program in Hematology, Oncology, and Transplantation at the University of Minnesota, where he was selected for the T32 academic research track. His research now examines mechanisms of immune escape by leukemias and lymphomas. Both his research interest and clinical practice have a particular focus on acute lymphoblastic leukemia. He joined the faculty at the University of Minnesota in 2021.

Research Summary

• Acute lymphoblastic leukemia
• Lymphoma
• Immune therapies

Teaching Summary

“Blood” coursework for medical students

Clinical Summary

Acute lymphoblastic leukemia; Lymphoma; Immune therapies

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

Research Summary

T cell responses in autoimmunity and chronic infections My laboratory studies CD8 and CD4 T cell responses to proteins, which are persistently present in an organism to elucidate how chronic interaction with cognate antigen impacts T cell selection, differentiation and survival. We observe and manipulate chronic pathogen or self-specific T cell responses over time by using MHC tetramers, adoptive transfer of transgenic T cells and fluorescence flow cytometry. We are currently interested in understanding what maintains the population of memory T cells specific for persistent pathogens, such as polyoma virus. In addition, we are interested in elucidating how tolerance is induced and maintained to intestinal protein, as breakdown of this can lead to diseases such as ulcerative colitis and Crohn's disease. By understanding these processes, we can learn how to manipulate the immune system for eradication of persistent infections, as well as interfering with the development and progression of autoimmunity.

Research Summary

Our research interests pertain to leukocyte biology with a current focus on natural killer (NK) cells. Various receptors expressed on the surface of leukocytes that are critical for their function can be rapidly downregulated in expression upon cell activation by “ectodomain shedding”. This process is primarily mediated by the membrane-associated metalloprotease ADAM17. Ectodomain shedding operates in part as a negative feedback mechanism to restrain leukocyte function and ADAM17 serves as a broad-acting regulatory checkpoint that controls NK cell activity in a polyfunctional manner. Our goal is to manipulate this process to enhance NK cell function in killing tumor cells and virus-infected cells. 
Experts@Minnesota Profile
PubMed Article List

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.