Digestive Diseases Innovative Awards (4 x $40,000):
The SDDRC has awarded pilot grants to promote innovative research in digestive diseases. This year's awardees are:
Parambir Dulai, MD
Assistant Professor, Department of Medicine
About the Awardee: Dr. Dulai is an early career physician-scientist with a specific research focus on clinical trial design, health outcomes, and translational and predictive medicine for inflammatory bowel disease (IBD). He completed his residency and chief resident training at Dartmouth and subsequently completed an NIH sponsored T32 gastroenterology research fellowship at UCSD. He went on to complete a dedicated IBD clinical fellowship at UCSD and a clinical trials fellowship at Robarts Clinical Trials. He is currently supported by an AGA Research Scholar Award and serves as the lead PI for a multi-national IBD health outcomes consortium.
Project Title: "Effects of hyperbaric oxygen on the microbiome"
Summary: We have demonstrated that hyperbaric oxygen, the delivery of high amounts of oxygen to the body, improves symptoms and healing of the colon for ulcerative colitis patients. Using stool samples from patients enrolled in these trials we observed a significant effect for hyperbaric oxygen on the gut microbiome composition and metabolism. We will now study how these microbial changes interact with the host immune system through animal model experiments. This work will help to create a better understanding of the interplay between hypoxia, microbes, and the immune system in ulcerative colitis.
Dannielle Engle, PhD|
Assistant Professor, The Salk Institute for Biological Studies
About the Awardee: Dr. Engle became an Assistant Professor at Salk Institute in 2019 after finishing her postdoctoral fellowship at Cold Spring Harbor Laboratory and Cambridge Research Institute. She completed her Ph.D. in Biology at UCSD and her BA in Biological Sciences and Asian and Middle Eastern Studies at Northwestern University. The research in the Engle lab focuses on the intersection between inflammation and cancer in the pancreas, building upon Engle’s discovery that the carbohydrate biomarker, CA19-9, causes pancreatitis and accelerates tumorigenesis using genetically engineered mouse models. Using mouse and organoid models, the Engle lab’s first goal is to dissect the downstream CA19-9 effector pathways that mediate reprogramming of the pancreatic microenvironment. In addition, Engle’s lab is also testing the therapeutic efficacy of CA19-9 targeted therapy for the treatment and interception of pancreatitis and pancreatic cancer.
"Interception of CA19-9 in Pancreatic Disease"
Summary: CA19-9 is a type of sugar that is commonly elevated in patients with pancreatic disease. We recently discovered that elevation of the sugar CA19-9 drives inflammation in the pancreas and increases the aggressiveness of pancreatic cancer. The effects of CA19-9 were reversible, suggesting that blocking CA19-9 may be a novel treatment option. In this proposal, we will uncover druggable regulatory mechanisms controlling levels of this sugar and test the efficacy of this treatment strategy in three-dimensional tissue culture models.
Jesus Rivera-Nieves, MD
Professor, Department of Medicine
About the Awardee: Dr. Rivera-Nieve's research focuses on novel treatment strategies for inflammatory bowel disease (IBD), based on modulation of leukocyte traffic. He began his medical training at the University of Puerto Rico, completed his Internal Medicine residency at the University of Maryland, and trained in Gastroenterology at the University of Virginia. Dr. Rivera-Nieve's research has been supported by NIDDK, CCFA, and VA Merit Research awards. He has published over 70 manuscripts in peer-reviewed journals and is a practicing gastroenterologist who cares for US Veterans who suffer from IBD.
Project Title: "A novel role for integrin αEβ7 for the optimal transcytosis of secretory IgA"
Summary: The integrins have emerged as a major therapeutic target for inflammatory bowel diseases (IBD). However, while vedolizumab (specific for α4β7) is effective in ulcerative colitis (UC); etrolizumab which targets the shared β7 subunit on both α4β7 and αEβ7 is not. We find an undescribed population of immunoglobulin (Ig)A+ plasma cells (PC) that contact or intercalate within intestinal epithelial cells (IEC) and express αEβ7. In these studies: we will 1. examine the role of αEβ7 for IgA transport. 2. Evaluate the significance of αEβ7 for the maintenance of luminal IgA in health and disease. 3. Define the maturation state of αEβ7+ PC via transcriptomic analyses. We propose that this undescribed subset of αEβ7+ PC physically engage IEC to directly relay IgA for luminal transport and speculate that this new role for the integrin may play a role on the differential efficacy of etrolizumab and vedolizumab in UC.
Sharpton, Suzanne, MD|
Assistant Professor, Department of Medicine
About the Awardee: Dr. Sharpton is a transplant hepatologist and Assistant Professor of Medicine in the Division of Gastroenterology and Hepatology at UCSD. Dr. Sharpton received her medical degree from the University of North Carolina School of Medicine. She subsequently completed Internal Medicine residency and chief residency as well as Gastroenterology and Transplant Hepatology fellowships at the University of California, San Francisco. As a Gastroenterology fellow at UCSF, Dr. Sharpton was supported by the NIH T32 training grant in Hepatology and completed the UCSF Training in Clinical Research Master’s Degree Program. Her research focuses on evaluating gut microbial-host interactions in the development and progression of obesity and nonalcoholic fatty liver disease. Dr. Sharpton’s research program is supported by an Alan Hofmann Clinical, Translational and Outcomes Research Award from the AASLD Foundation.
Project Title: "Novel metagenomic and metabolomic signature of PNPLA3-associated nonalcoholic steatohepatitis"
Summary: Nonalcoholic fatty liver disease is now the leading cause of chronic liver disease worldwide, affecting up to 25% of the population. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease characterized by inflammation and hepatocyte injury, is associated with the development of cirrhosis and hepatocellular carcinoma. Despite the high prevalence of NASH, effective therapeutic options are lacking. A growing body of evidence of suggests pathogenic contributions from both the gut microbiome and genetic susceptibility. It was recently discovered that a gut microbial signature, derived from metagenomic sequencing and metabolomics, is associated with advanced fibrosis and cirrhosis in NASH. One of the strongest genetic contributors to NASH is a variant in the Patatin-like phospholipase 3 (PNPLA3) gene, which has been shown to portend a significantly higher risk of cirrhosis and liver-related mortality. However, the underlying mechanisms by which either gut dysbiosis or the PNPLA3 gene variant contribute to the development of NASH have not been fully elucidated. This proposal aims to characterize the gut microbiome in PNPLA3-associated NASH and will yield preliminary data needed to ultimately decipher gut microbe-host communication pathways in the pathogenesis of NASH.
Jon I. Isenberg Fellowship Award ($40,000):
The Isenberg Endowed Fellowship jointly awarded by the Pilot/Feasibility Program of the San Diego Digestive Diseases Research Center and the Hellman Family Foundation. The fellowship, given in honor of the late Dr. Jon Isenberg 1979-1993 to promote Dr. Isenberg's lifelong research interests including intestinal epithelial ion transport mechanisms, mucosal defense, peptic ulcer disease, and cystic fibrosis, as applied to the intestine, liver, and biliary system.
Cristina Llorente, PhD
Assistant Adjunct Professor
About the Awardee: Dr. Llorente graduated from the Autonomous University of Madrid with a PhD in Biochemistry, Molecular Biology, and Biomedicine. After her doctorate, Dr. Llorente completed an internship at Dr. Jerrold Olefsky’s laboratory at UC San Diego, studying the pathogenesis of diabetes and obesity. As a postdoctoral fellow in Dr. Schnabl’s laboratory, her focus was to understand the influence of microbiota in liver diseases. Dr. Llorente’s long-term goal is to build a research program dedicated to mechanistically understand the role of host-microbiota interactions in modulating inflammation, the immune system, intestinal homeostasis, to decipher the cellular and molecular mechanisms involved in the progression of liver diseases, and to discover therapies and molecular targets to alleviate it. Dr. Llorente would like to understand, how its dysregulation orchestrates the development of liver pathologies.
Project Title: "Goblet cells and intestinal immune response in alcohol-associated liver disease"
Summary: Alcohol consumption is the 7th leading risk factor for death worldwide. Alcohol-associated liver disease is the most prevalent ethanol-related illness and is the major cause of advanced liver disease and liver transplantation in Europe and the United States. There is no treatment for alcohol-associated liver disease. Ethanol abuse is associated with intestinal dysbiosis and bacterial overgrowth. Microbiota alterations lead to intestinal barrier dysfunction, facilitating translocation of viable bacteria and microbial products to mesenteric lymph nodes (MLN) and liver, which causes inflammation and progression of liver disease. Increased translocation of microbial products activates the mucosal immune system and secretion of inflammatory mediators, amplifying barrier dysfunction. In turn, the host immune system influences the intestinal microbiota composition. The effect of chronic ethanol overuse on the LP-immune system remains to be fully characterized. This proposal will characterize the implication of goblet cells-mediated regulation of the LP-immune response and the impact in alcohol-associated liver disease in mice and in patients with alcohol use disorder.