Targeting Intestinal Epithelium to Promote Healing in Inflammatory Bowel Disease

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PROJECT SUMMARY/ABSTRACT Approach: I will focus on the NR5A nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2), increasingly recognized for its roles in cell growth and its anti-inflammatory transcription profile. Mice lacking intestinal LRH-1 knockout show increased mucosal damage and inflammatory markers in IBD models. I hypothesize that loss of LRH-1 will impair epithelial renewal and response to injury, and that enhanced LRH-1 expression will dampen intestinal inflammation and speed mucosal healing. I have developed an ex vivo intestinal organoid culture (enteroid) system to study epithelial responses to injury. The enteroid system allows me to directly address the role of LRH-1 in intestinal epithelial pathophysiology by using conditional mouse genetic models that eliminates LRH-1 in the intestinal epithelium (Villin-CreER). I have adapted the adeno-associated virus (AAV) system to enable expression of human LRH-1 and important LRH-1 mutations in the enteroid system to further probe LRH-1-mediated epithelial function. I will use in vivo IBD models with both conditional LRH-1 knockout and overexpression to build upon my ex vivo studies, and to define the role of LRH-1 in epithelial injury and inflammatory response. My work will determine if LRH-1 activation is sufficient to blunt immune-mediated mucosal injury and ask if LRH-1 can be targeted for IBD drug development. I believe that the questions being asked and the experimental models outlined in this Mentored-based K08 application are exciting and highly relevant to my clinical interests in inflammatory intestinal disorders. Candidate & Rationale: I am a dual-degree physician scientist MSTP graduate trained in gastroenterology and pharmacology. In this proposal I seek to understand the molecular pathways that govern bowel homeostasis and the adaptive mechanisms that drive injury response. In the intestine, inflammatory responses are mediated by both metabolic and environmental cues. Inflammatory bowel disease (IBD) is a chronic disease that affects both adults and children alike, imposing significant morbidity and healthcare costs. Understanding how the intestinal epithelium self-renews and maintains its integrity in the face of inflammatory damage is key to the development of novel therapies for intestinal disease. My ultimate goal is to head an independent research program focused on translational intestinal disease models and therapeutic design. Career goals: Through the framework delineated by this proposal, I will establish an independent research program dedicated to understanding intestinal pathophysiology and the development of novel therapeutics. The research plan described herein is designed to expand my expertise into new arenas of animal genetics and disease modeling. This is consistent with my long-term goals of translational science, bringing discoveries from my laboratory back to benefit my patients. The mentoring I will receive by my Advisory Committee coupled with the career development workshops at UCSF such as grant and manuscript writing, will foster both my professional and scientific development. Environment: I have identified a strong mentoring team lead by Dr. Holly Ingraham, a leader in nuclear receptor biology. Dr. Averil Ma, an expert in IBD and animal models of colitis, and Dr. Ophir Klein, a physician scientist with epithelial stem cell expertise, round out my Advisory Committee with complementary skill sets. To enhance my research training, I will engage in didactic coursework in immunology, advanced light microscopy, high throughput data analysis, and the responsible conduct of research. UCSF provides a stimulating environment for the pursuit of science with a highly collaborative network of investigators. The Department of Pediatrics and the Division of Gastroenterology each have a long history of developing future leaders in basic and clinical science. In summary, as a highly motivated clinician scientist, my ultimate goal is to develop an independent basic and translational research program focused on intestinal disorders. This proposal provides necessary training in research coupled with a strong mentoring plan to help me achieve success.