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Targeting Intestinal Epithelium to Promote Healing in Inflammatory Bowel Disease

针对肠上皮促进炎症性肠病的愈合

基本信息

批准号：
9180524
负责人：
James Bayrer
金额：
$ 15.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-18 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180524
关键词：
Address Adult Advisory Committees Affect Animal Disease Models Animal Genetics Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Back Basic Science Binding Biology Breeding Cells ChIP-seq Child Childhood Chronic Chronic Disease Clinical Clinical Sciences Colitis Complement Coupled Cues Data Data Analyses Dependovirus Development Diagnosis Disease Disease model Dissection Drug Targeting Educational workshop Engineering Environment Epithelial Epithelial Cells Experimental Models Fostering Functional disorder Future Gastroenterologist Gastroenterology Gastrointestinal tract structure Gene Expression Gene Targeting Genes Genetic Models Genetic Transcription Goals Grant Growth Head Healed Health Care Costs Holly Homeostasis Human Immune Immunology Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Injury Intestinal Diseases Intestines Knock-out Knockout Mice Laboratories Lead Ligand Binding Ligands LoxP-flanked allele Manuscripts Mediating Mentors Metabolic Modeling Molecular Morbidity - disease rate Mus Mutation NR5A2 gene Natural regeneration Nuclear Receptors Organoids Pathway interactions Patients Pharmacology Physicians Predisposition Production Recording of previous events Research Research Personnel Research Training Resistance Review Committee Role Science Scientist Speed Staging Stem cells Steroids Suggestion Sulfonic Acids System Techniques Testing Therapeutic Tight Junctions Training Transcript Translational Research Trinitrobenzenes Work Writing base career career development cell growth design drug development genetic manipulation healing humanized mouse immune function in vivo in vivo Model inflammatory marker interest intestinal crypt intestinal epithelium light microscopy mouse model mutant new therapeutic target novel novel therapeutics overexpression pediatric department programs receptor response response to injury responsible research conduct self-renewal skills success tissue culture transcriptome sequencing villin

项目摘要

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.

项目总结/文摘