Research

Steer’s laboratory has been involved in three major areas of research during the last five years.

1. The Sleeping Beauty (SB) transposon system functions via a cut-and-paste mechanism catalyzed by the binding of SB transposase to inverted repeats/direct repeats (IR/DRs) of the mariner transposon. It excises the relevant transgene from the transposon at the IR/DRs and inserts the element into random TA dinucleotide sites within the genome. They are applying SB as a gene therapy vector to a variety of different animal disease models, including liver, bone marrow and brain disorders. Steer's laboratory is also interested in characterizing the effects of SB transposition on genomic methylation and histone acetylation.
2. Using ursodeoxycholic acid (UDCA), a hydrophilic bile acid, as a potent antiapoptotic agent. They have used UDCA as a therapeutic agent to treat transgenic models of Huntington’s disease and retinitis pigmentosa as well as acute stroke, spinal cord injury, myocardial infarction, and acute renal failure. Steer's laboratory continues to study basic mechanisms and translational applications of UDCA. Of note, the South Korean FDA has recently approved its use for the treatment of ALS.
3. Characterizing the role of microRNAs in gene regulation for a number of different target organs and stem cell populations. In particular, they have identified specific microRNAs that may be involved in the progression of colon from polyp to cancer; as well as their role in the regenerating liver. The studies are both basic and translational in nature. They are also identifying specific microRNAs as biomarkers of disease that can be assayed in blood. Most notably, they have recently discovered a unique nuclear profile of mature microRNAs; and a subset of microRNAs in mitochondria that may act as a rheostat for the control of apoptosis.

Over the past eight years, Steer’s lab has also focused on regenerative medicine, and research to create human livers in pigs for transplantation. The approach utilizes a combination of gene editing and a technology referred to as blastocyst complementation. The ultimate goal is to create human livers in pigs that are immunology identical to the recipient, thereby not requiring the use of immunosuppression…a paradigm shift in organ transplantation.

Song’s lab focuses on the molecular mechanisms of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) and their immunotherapies. There are four main areas of focus for Song’s lab:

1. The underlying mechanism by which NAFLD progresses to HCC.
2. Roles of Kupffer cells in modulating the pathogenesis of NAFLD and HCC.
3. MicroRNA-based immunotherapy for the treatment of NAFLD and HCC.
4. Regulation of microRNA biogenesis in NAFLD and HCC.

Current Research Direction

The underlying mechanism by which NAFLD links to HCC. Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality that runs almost parallel to its incidence. The incidence of HCC that was once considered a rare cancer is increasing dramatically in the US. However, it is estimated that 15-50% of HCC patients develop HCC in the absence of eminent etiological factors such as hepatitis viral infection in the Western world. One major cause of this rising incidence is non-alcoholic fatty liver disease (NAFLD). NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and HCC. The incidence rate of NAFLD has been rapidly increasing due to the prevalence of obesity. Despite a strong association between NAFLD and HCC, the underlying mechanisms by which NAFLD patients develop HCC are not known. We are using single-cell RNA-seq, spatial transcriptomic approach, novel mouse models and molecular and cellular approaches to investigate the roles of microRNAs in linking NAFLD to HCC.  

MicroRNA-based immunotherapy of liver cancer. Despite the impressive response of immunotherapies in some cancers, HCC patients have not benefited from immunotherapies. One major reason is that the liver has higher physiological immune tolerance to antigens. Another consideration is that multiple pathways participate in HCC development, establishing a refractory immune tolerogenic tumor microenvironment (TME), thereby leading to resistance to single immunotherapy. MicroRNAs (miRNAs), a class of naturally-occurring small non-coding RNAs, function by simultaneously fine tuning multiple pathways. During the evolution, a stable interactome between miRNAs and their targets is formed to maintain the physiological homeostasis. These characteristics of miRNAs allow us to speculate that miRNAs might be able to precisely modulate immune homeostasis and potentially overcome limitations and challenges of current immunotherapies. We are identifying miRNAs that are critical regulators of immune homeostasis during the pathogenesis of NAFLD and HCC, in addition to developing miRNAs as a novel, effective and accurate immunotherapy without adverse effects that are inherent in the routine immunotherapies.

Roles of Kupffer cells (KCs) in preventing immune escape during the pathogenesis of HCC. KCs, liver resident macrophages, account for ~15% of the liver cell population. KCs represent a major source of chemoattractant molecules, indicating that KCs might be involved in maintaining immune homeostasis. However, their role in HCC is rarely described. We have established that KCs are a critical therapeutic target for the treatment of HCC. We are determining the response of KCs by analyzing secretome and transcriptome of KCs during the pathogenesis of HCC, establishing the interact network between KCs and other immune cells, and finally elucidating the underlying mechanism of immune escape in HCC. Our findings will fill the knowledge gap regarding the role of KCs in preventing immunosuppression and elucidate how KCs prevent immune escape and HCC development. By elucidating the mechanisms involved, we intend to develop KCs as a new therapeutic target against HCC.

Elucidating how hepatic insulin resistance simultaneously drives hepatosteatosis and hyperglycemia. In normal livers, insulin drives lipogenesis and inhibits glucose production. Insulin resistance is the major cause of hepatosteatosis and hyperglycemia. However, the paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce triglycerides, has been central to the pathophysiology of type 2-diabetes. Our goal is to resolve this long-standing mystery.

Synergistic role of microRNAs and their host genes in maintaining lipid homeostasis in NAFLD. miRNA genes are categorized based on genomic location including, intronic and exonic miRNAs in non-coding transcripts and intronic and exonic miRNAs in protein-coding transcripts. It is widely-accepted that both exonic and intronic miRNAs in protein-coding transcripts share the transcription machinery with their host genes. One such miRNA is miR-378 that is embedded within the first intron of Ppargc1β. Ppargc1β encodes PGC1β, a transcriptional coactivator that regulates mitochondrial biogenesis, thermogenesis, and lipid metabolism. Liver-specific ablation of Ppargc1β leads to reduced FAO and VLDL secretion and subsequently hepatosteatosis. However, it is unknown, how PGC1β and miR-378, which are located in the identical Ppargc1β-miR-378 genomic locus, synergistically and coordinately modulate hepatosteatosis, inflammation and fibrosis. Completion of this study will provide a novel insight into the transcription mechanism(s) of miRNAs and their host genes, which maximizes the genetic information to fit the complexity of NAFLD pathogenesis.
 

Dr. Piet de Groen is an NIH-funded clinical investigator and international expert in medical informatics, primary liver cancers and colonoscopy.

His endoscopic research is focused on measuring what happens during colonoscopy. Together with collaborators at Iowa State University and the University of North Texas he has created a first-of-a-kind new software system that automatically captures and analyzes “inside-the-patient” video information of medical procedures performed via endoscopy. At present he is studying patient- and endoscopist-specific features, including quality of the colon preparation and effort of the endoscopist to visualize mucosa, remove remaining fecal material and adequately distend the colon. Another focus of study is automated measurement of the degree of mucosal inflammation as seen in inflammatory bowel diseases.

The ultimate goal of his endoscopic research related to colonoscopy is a fully automated quality control system that provides real-time feedback to the endoscopist and ensures individualized healthcare by virtually guaranteeing a high quality examination for each patient. Another goal is to extend the technology to other organs examined using endoscopy equipment and combine the information obtained from the optical signal with information derived from other imaging modalities.

Co-directed by Dr. Byron Vaughn and Dr. Eugenia Shmidt, the Inflammatory Bowel Disease (IBD) program engages in all facets of research with the goal to improve the care and eventually cure IBD. The IBD program studies how to use and develop microbiota based therapeutics to treat and prevent IBD. There are also a number of studies on how various treatments (traditional and nutritional based) affect the gut microbiome in IBD. Optimizing current IBD therapy through therapeutic drug monitoring is another key focus of the IBD program. The IBD program studies IBD in pregnancy, including safety of therapies in pregnancy and disease control over the course of a pregnancy. Industry sponsored research is also available including phase III and IV trials in various sub-types of IBD.

The UMN Esophageal Disorders Program is led by Dr. Joshua Sloan. Dr. Sloan’s research interests include Eosinophilic Esophagitis, esophageal motility disorders, Esophageal Lichen Planus, and Functional Lumen Imaging Probe among other topics.

Dr. Sloan is currently active on a few different research projects, including:

• Ongoing retrospective multicenter study focusing on Esophageal Lichen Planus
• Clinical trial on Eosinophilic Esophagitis
• Esophageal motility in the setting of lung transplant patients
• Retrospective eosinophilic esophagitis projects
• Retrospective analysis evaluating patients with Fanconi Anemia

Beyond Dr. Sloan’s current research work, the UMN Esophageal Disorders Program is interested in collaborating with dieticians and GI clinical psychologists to evaluate how their involvement in patient care may impact outcomes

Led by Dr. Alex Khoruts, The University of Minnesota Microbiota Therapeutics Program pioneered the use of Intestinal Microbiota Transplantation (IMT) to restore intestinal health and created the first stool donor program worldwide. There are many potential clinical applications of microbiota therapeutics. Our program is committed to support academic trials for a variety of applications. Some of the ongoing work is in the areas of ulcerative colitis, leukemia, pitt hopkins syndrome, autism, advanced liver disease, and others.

The Division of Gastroenterology, Hepatology, and Nutrition has 11 researchers and research managers whose time is devoted to the Microbiota Research and Therapeutics Team.

Hijab Zehra, Graduate Research Assistant
Lulu Chen, Clinical Research Associate
Parker Haselhorst, Research Scientist
Amanda Kabage, Research Program Manager and Regulatory Specialist
Nataliia Kuchma, Gastroenterologist and Clinical Research Associate
Sharon Lopez, Clinical Research Associate and Regulatory Specialist
Amanda Mandarino, Gastroenterologist and Clinical Research Associate
Mike Matson, IMT Donor Program Coordinator & Research Scientist
Maradi Pho, GMP Operations Manager
Ruma Raghuvanshi, Postdoctoral Researcher
Campbell Sampson, Research Scientist

Dr. Thomas Leventhal is an advanced liver disease and critical care expert. Dr. Leventhal's research interests include acute liver failure, critical care for those with advanced liver disease, and cost of care and pharmacotherapy for those with liver disease. Dr. Leventhal is currently active working on the following research projects, including

• Acute Liver Failure outcomes through an NIH funded Acute Liver Failure Study Database
• Cost of care and pharmacotherapy - including membership in a Drug Cost consortium studying the costs of generic medications in the United States and studying financial toxicity of commonly used medications in patients with cirrhosis
• Outcomes of patients with cirrhosis admitted to the intensive care unit

The majority of the Division's funded clinical research is in the area of viral hepatitis. There are currently four funded research protocols for the management of patients with hepatitis C. Dr. John Lake is involved in clinical research studies which focus on the treatment of hepatitis C with pegylated interferon and ribavirin.

In addition, the Division is an active participant in the Midwest Hepatitis Study Group, which is a consortium of investigators interested in the management of patients with chronic viral hepatitis. Dr. John Lake is also a co-investigator on 2 NIH-funded clinical research protocols, one on the area of primary biliary cirrhosis (M. Eric Gershwin, PI) and one in the area of non-alcoholic steatohepatitis (Elizabeth Parks, PI).

The Gastroenterology Division maintains an ongoing interest in the use of TIPS (transjugular intrahepatic portal systemic shunt) for management of complications of portal hypertension.

Led by Dr. Guru Trikudanathan, MBBS, the section is active in research focusing on diabetes and pancreatitis and genetic factors that predispose to pancreatitis or diabetes that affect TPIAT outcomes. Listed below are current studies:

• Dr. Guru Trikudanthan is the Co-Principal investigator at University of Minnesota for Diabetes Related to Acute pancreatitis and its Mechanisms (DREAM) and The IMaging Morphology of Pancreas in DIabetic PatieNts following AcutE PaNcreaTitis (IMMINENT) study from NIH/NIDDK as a part of the Type 1 Diabetes in Acute Pancreatitis  Consortium (T1APDC) UO1. DREAM study is a prospective longitudinal observational clinical study to investigate the incidence, etiology and pathophysiology of diabetes mellitus following acute pancreatitis. A biorepository of longitudinally collected samples from participants will be developed for use in future translational studies. IMMINENT study aims to assess morphologic changes on MRI as a imaging biomarker to predict who will develop diabetes following acute pancreatitis.
• Dr. Guru Trikudanthan is also the principal investigator of GEN POST study which is funded by the American Pancreas Association Young Investigator award. Gen POST capitalizes on POST (the Prospective Observational Study of Total pancreatectomy and islet autotransplantation) study infrastructure funded by NIDDK, to address specifically how outcomes after TPIAT are determined by genetic factors that predispose to pancreatitis or diabetes or that affect opioid responsiveness. GEN POST hopes to predict how genotype affects phenotypic response to TPIAT.
• Dr. Guru Trikudanathan is also the coinvestigator at University of Minnesota for PROCEED study from NIH/NIDDK as part of the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) (UO1). PROCEED is the first prospective observational cohort study for chronic pancreatitis in the United States which aims to define disease progression and develop a platform to conduct translation and mechanistic studies in chronic pancreatitis. This study will enroll adults at different stages of chronic pancreatitis and provide the most accurate and reliable estimate to date on progression of chronic pancreatitis. The established cohort and biorepository will also facilitate development of new strategies for diagnosis, methods to monitor disease progression and treatment of chronic pancreatitis.

ERCP research in the section is led by Dr. Martin Freeman, MD. Dr. Freeman has published over 30 textbook chapters and 250 peer reviewed articles, including several index papers for which he was the principal author: a multicenter study on ERCP complications in the New England Journal of Medicine, a multivariable model for prediction of post ERCP pancreatitis in Gastrointestinal Endoscopy, guidelines for the management of acute pancreatitis in the American Journal of Gastroenterology, and a consensus paper and a systematic review on interventions for necrotizing pancreatitis in the Pancreas, and recently in Gastroenterology.

Through work led by Dr. Stuart Amateau MD, PhD, the advanced endoscopy section has collaborated with regional and national partners to develop novel devices and techniques to improve patient care. Specific examples of innovation include a refined approach to malignant obstruction of the bile duct that is not accessible by traditional endoscopic retrograde cholangiopancreatography ERCP and development of a novel means to deploy hemostatic particles for the treatment of gastrointestinal bleeding using considerably less expensive components.

Led by Dr. Nabeel Azeem, MD, the section is active in research on endoscopic resection of gastrointestinal neoplasia, endoscopic therapy for achalasia, third space endoscopy, and EUS guided treatment of gastric and ectopic varices.

Led by Dr. Shawn Mallery, MD, the advanced endoscopy section is active in research aimed at discovering the effectiveness and use cases of interventional EUS to improve patient diagnosis and reduce the need for traumatic surgery. Of note, recent publications have:

• evaluated the impact of telepathology and operator experience on endobronchial ultrasound- and endoscopic ultrasound-guided fine-needle aspiration (EBUS-/EUS-FNA)
• measured the effectiveness of EUS-guided pancreaticogastrostomy (PG) as an alternative to surgery to drain ducts for treatment of disconnected pancreatic duct syndrome (DPDS)
• described the clinical, radiologic, cytologic, gross and histologic features of diagnosing mediastinal ganglioneuroma by transesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA)
• discovered a potential key role for fine-needle aspiration cytology in the preoperative diagnosis of pancreatic and other intra-abdominal desmoid tumors

The section’s faculty are active in research on the early diagnosis and management of chronic pancreatitis and the management of and interventions for necrotizing pancreatitis. In addition, studies are ongoing with a focus on biliary disease, obstruction, strictures, and leaks. These studies highlight treatments and procedures including ERCP, stents, and lithotripsy devices. Research is also focused on pancreatic endo-therapy through endoscopic ultrasound and endoscopic retrograde cholangio-pancreatography for management of complex pancreatic and biliary conditions.

COVID-19 & Acute Pancreatitis. The advanced endoscopy section was the first to publish a significant increase in both the morbidity and mortality of patients with acute pancreatitis that were also found to have evidence of SARS-CoV-2 infection when compared to an uninfected cohort. The study demonstrated a higher incidence of multiorgan failure and persistent organ failure in the infected group prompting further investigations into a relationship with the inflammatory cascade.

Total Pancreatectomy and Islet Autotransplantation. The section has recently studied the effects that preoperative sarcopenia has on islet cell yield following TPIAT. In addition, studies have been conducted on the alterations in enteroendocrine hormones, reduced bone mineral density, and long term diabetes outcomes after TPIAT.