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The role and regulation of deep crypt secretory cells in colitis

隐窝深部分泌细胞在结肠炎中的作用及调控

基本信息

批准号：
10526024
负责人：
Michael Andrew Schumacher
金额：
$ 15.9万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10526024
关键词：
Acute Advisory Committees Affect Area Automobile Driving Award Biology Cell Count Cell Differentiation process Cell Line Cell Survival Cell physiology Cells Cellular biology Chronic Colitis Colon Data Development Development Plans Doctor of Philosophy Epithelial Epithelial Cells Foundations Funding Goals Health Homeostasis Host Defense Human Immune Immune response In Vitro Inflammation Inflammatory Bowel Diseases Institution Interleukin-13 Intestines K-Series Research Career Programs Knockout Mice Mentors Modeling Mus Organoids Pathway interactions Patients Peptides Pharmacology Population Principal Investigator Production Proteins Recovery Regulation Repression Research Research Personnel Resistance Role Secretory Cell Severities Shapes Signal Transduction Source Testing Training Support United States National Institutes of Health Western Blotting Work base career career development colonic crypt cytokine design experimental study gain of function healing immune activation immune function in vivo inhibitor insight intestinal epithelium mouse model new therapeutic target progenitor research and development response spatiotemporal stem therapeutic target tool transcriptomics

项目摘要

PROJECT SUMMARY Deep crypt secretory (DCS) cells are an understudied lineage of secretory cells residing in the colonic crypt base with unknown roles in colitis. In preliminary data, I show that DCS cells express a class of proteins known as host defense peptides (HDPs) that can influence key epithelial (e.g. differentiation, barrier integrity) and immune functions. Despite clear demonstrations of altered colonic secretory cell numbers and HDP levels in inflammatory bowel disease (IBD), the mechanisms regulating DCS cells and HDPs are poorly understood. This proposal is designed to identify the mechanisms driving DCS cell differentiation and HDP production in colitis, and determine the role of these factors in regulating epithelial and immune functions. Using a mouse model with elevated DCS cell numbers, I am proposing coordinated in vivo and in vitro approaches to understand the mechanisms underlying DCS cell differentiation and HDP expression in the colon (Aim 1) and to test how altered DCS cell-derived HDPs affect colonic homeostasis and acute and chronic colitis severity (Aim 2). This work will be accomplished with new expertise obtained in advanced transcriptomic studies and epithelial lineage tracing in models of colitis by working with my team of co-mentors and advisory committee. This work will advance our understanding of the cellular mechanisms that drive intestinal epithelial remodeling in colitis, and thus may reveal new potential therapeutic targets for IBD and other intestinal inflammatory disease. The research and career development plan, generated in concert with my mentors and advisory committee, will provide the training and support necessary to become an independent investigator at an academic research institution.

项目总结