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Enteric CRF Receptor Signaling in Stress-Induced Intestinal Barrier Dysfunction

应激性肠屏障功能障碍中的肠道 CRF 受体信号传导

基本信息

批准号：
7895717
负责人：
Adam Moeser
金额：
$ 12.02万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895717
关键词：
Address Animal Model Animals Binding Cell Communication Cell Culture Techniques Chronic Chymase Clinical Coculture Techniques Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Cromoglicic Acid Development Diarrhea Disease Effector Cell Enteral Epithelial Epithelium Event Exposure to Family suidae Functional disorder Future Gastroesophageal reflux disease Gastrointestinal Diseases Health Care Costs Homeostasis Human Hypothalamic structure IgE In Vitro Inflammatory Bowel Diseases Intestinal Diseases Intestines Irritable Bowel Syndrome Lead Life Link Mediating Mediator of activation protein Modeling Molecular Molecular Genetics Mucous Membrane Mus Neuraxis Neuropeptides Onset of illness Organ Parasitic infection Pathogenesis Peripheral Permeability Pharmaceutical Preparations Physiological Play Property Psychological Stress Psychosocial Stress Receptor Activation Receptor Signaling Regulation Research Research Personnel Role Signal Pathway Signal Transduction Stabilizing Agents Stress System Testing Tissues Translational Research Tryptase United States allergic response base biological adaptation to stress body system design gastrointestinal improved in vivo intestinal epithelium intraperitoneal mast cell mouse model productivity loss programs public health relevance receptor research study response stressor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Stress-induced intestinal disorders such as Irritable Bowel Syndrome are the most economically burdensome gastrointestinal diseases known. The long-term objective of the research proposed in my K08 application is to study the basic mechanisms of psychological stress-induced breakdown of intestinal barrier function which is a key underlying event responsible for activation of intestinal disease. In previous animal studies, we demonstrated that enteric corticotrophin releasing factor (CRF) and its receptors play a major role in stress-induced breakdown of intestinal barrier function characterized by increased intestinal permeability. My recent findings revealed an important role of intestinal mast cells (MCs) as key effector cells in this mucosal stress response. We hypothesize that psychological stress stimulates enteric release of CRF that binds to intestinal MCs, via CRF receptors, triggering MC tryptase release and breakdown in intestinal barrier function. We will test this hypothesis in three Specific Aims: 1) Determine if CRF activates MCs via CRF receptors resulting in increased intestinal permeability, 2) Determine if MC tryptase is the key MC mediator triggering increases in intestinal permeability, and 3) Determine if CRF-MC signaling pathways mediate psychological stress-induced barrier dysfunction in vivo. In Specific Aims 1 and 2, we will utilize in vitro MC-intestinal epithelial coculture systems to study the interactions between CRF and CRF receptors expressed on MCs and how these interactions initiate signaling events that lead to disturbed intestinal epithelial barrier function. We will employ a variety of molecular, genetic, and pharmacological approaches in this model to test my hypothesis. In Specific Aim 3, we will utilize a mouse model of early life psychological stress to induce permanent disturbances in colonic mucosa barrier function thus mimicking stress-related disease in humans. We will utilize MC-deficient mice combined with molecular-based approaches to determine the definitive role of CRF-MC signaling in psychological stress induced barrier dysfunction. PUBLIC HEALTH RELEVANCE: This research will improve our understanding of the basic mechanisms of CRF-MC signaling and should have important implications in the future design of targeted therapeutic strategies to treat these costly disorders.

描述（由申请人提供）：