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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：
8484394
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484394
关键词：
Address Animal Model Animals Basic Science 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 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 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）：应激诱导的肠道疾病如肠易激综合征是已知的最经济负担的胃肠道疾病。我在K 08申请中提出的研究的长期目标是研究心理应激诱导的肠道屏障功能破坏的基本机制，这是导致肠道疾病激活的关键潜在事件。在以前的动物研究中，我们证明了肠促肾上腺皮质激素释放因子（CRF）及其受体在应激诱导的肠屏障功能的破坏中起着重要作用，其特征在于肠通透性增加。我最近的研究结果揭示了肠道肥大细胞（MC）作为关键效应细胞在这种粘膜应激反应中的重要作用。我们推测，心理应激刺激肠释放CRF结合到肠道MC，通过CRF受体，触发MC类胰蛋白酶释放和肠道屏障功能的崩溃。我们将在三个特定目的中检验这一假设：1）确定CRF是否通过CRF受体激活MC，导致肠通透性增加，2）确定MC类胰蛋白酶是否是触发肠通透性增加的关键MC介导剂，和3）确定CRF-MC信号传导途径是否介导体内心理应激诱导的屏障功能障碍。在具体目标1和2中，我们将利用体外MC-肠上皮共培养系统来研究CRF和MC上表达的CRF受体之间的相互作用，以及这些相互作用如何启动导致肠上皮屏障功能紊乱的信号事件。我们将在这个模型中采用各种分子、遗传和药理学方法来验证我的假设。在具体目标3中，我们将利用早期生活心理应激的小鼠模型来诱导结肠粘膜屏障功能的永久性障碍，从而模拟人类的应激相关疾病。我们将利用MC缺陷小鼠结合分子基础的方法来确定CRF-MC信号转导在心理应激诱导的屏障功能障碍中的决定性作用。公共卫生关系：这项研究将提高我们对CRF-MC信号传导基本机制的理解，并对未来设计治疗这些昂贵疾病的靶向治疗策略具有重要意义。