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Decoding LRH-1 Activity in Gut Regeneration and Differentiation

解码肠道再生和分化中的 LRH-1 活性

基本信息

批准号：
10726639
负责人：
James Bayrer
金额：
$ 12.16万
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：
2021
资助国家：
美国
起止时间：
2021-06-14 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726639
关键词：
Address Adult Autoimmune Diseases Automobile Driving Binding Biochemical Biological Models Biology CRISPR-mediated transcriptional activation Cell Differentiation process Cell Lineage Cell Maintenance Cell Proliferation Cell Survival Cells Chromatin Complement Complex Coupled Disease Drug Receptors Enteroendocrine Cell Environment Epithelial Cells Epithelial Physiology Epithelium Epitopes Equilibrium Evaluation Experimental Designs Funding Genes Genetic Genetic Transcription Goals Health Hormones Infection Inflammatory Injury Intestines Investigation Knock-out Knowledge Liquid substance Maps Mediating Modeling Molecular Mucous Membrane NR5A2 gene Natural regeneration Nuclear Receptors Organoids Outcome Pharmacotherapy Physiology Population Positioning Attribute Post-Translational Protein Processing Process Production Property Regulation Regulator Genes Research Role Secretory Cell Shapes Signal Transduction Stereotyping Sumoylation Pathway Supporting Cell Surface Surveys Technology Therapeutic Tissues Work base cell type crypt cell design directed differentiation drug development enteritis epithelial repair epithelial stem cell follow-up gastrointestinal epithelium healing in vivo injury recovery insight intestinal crypt intestinal epithelium intestinal injury mouse model mutant novel overexpression pharmacologic pluripotency factor progenitor programs receptor function repaired response to injury restoration stem stem cell division stem cell population stem cell survival stem cells stemness tool transcription factor

项目摘要

Project Summary/Abstract Background: The primary epithelial stem cell in the intestine has been known for over a decade, leading to important observations in epithelial renewal and injury recovery. These fundamental studies have demonstrated that the intestinal epithelium is a balanced continuum between stemness in the crypt base and differentiation towards the mucosal surface, with complex signaling networks influencing stemness and fate of the differentiating progenitor cells. Several groups have now shown that destruction of intestinal stem cells and/or extensive epithelial damage can be repaired by the dedifferentiation of progenitor cells. Thus, the balance between stemness and differentiation can be tipped by as yet undefined molecular mechanisms. We discovered that the nuclear receptor Liver Receptor Homolog-1 (LRH-1; NR5A2) is essential for both stem cell maintenance and for directing differentiation of the highly specialized enteroendocrine cell lineage. Therefore, this unusual transcription factor has dual roles promoting stemness and cell differentiation, making it an attractive target for elucidating the mechanisms responsible for gut epithelial renewal and healing. Approach: In this application, we will 1) determine the contribution of LRH-1 to epithelial repair and stem cell restitution in enteritis models, 2) determine how SUMOylation of LRH-1 modulates receptor function in stem and progenitor cells, and 3) determine and validate the cell-specific gut LRH-1 “targetome.” We will accomplish this through the use of lineage-traced mouse models and novel implementations of the intestinal organoid platform. Following successful completion of our aims, we will have mechanistically evaluated the contribution of a druggable nuclear receptor to 1) balancing stem cell renewal, differentiation, and restitution of damaged epithelium 2) provided the first ever detailed evaluation of SUMOylated LRH-1 in the gut, and 3) generated a bona fide LRH-1 gut targetome that will be invaluable for receptor drug development. Goals: This proposal is designed to expand upon a key finding uncovered during my funded K08 investigation and advance our mechanistic understanding of how the gut balances stemness vs differentiation during normal and diseased states. Underlying this work is our hypothesis that LRH-1 is differentially modulated within unique cellular contexts in stem and progenitor cells to drive diverse gene programs simultaneously supporting cell renewal and specialized cell differentiation. Our experiments are designed to maximally exploit the extraordinary confluence of intestinal epithelial physiology and nuclear receptor biology framed by LRH-1.

项目总结/文摘