Neural Priming of CRF-Mast Cell Signaling

CRF-肥大细胞信号传导的神经启动

基本信息

批准号：
8574011
负责人：
Adam Moeser
金额：
$ 7.58万
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：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574011
关键词：
Abdominal Pain Animals Award CRF receptor type 1 Cell Communication Cell Degranulation Chymase Coculture Techniques Communication Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Defect Development Diarrhea Disease Epithelial Event Funding Gastrointestinal Diseases Goals Homeostasis Human Hypothalamic structure Immune Immune System Diseases Inflammation Inflammatory Bowel Diseases Injury Intestines Irritable Bowel Syndrome Life Stress Mediating Mediator of activation protein Molecular National Institute of Diabetes and Digestive and Kidney Diseases Nerve Nervous system structure Neurons Pathogenesis Peptides Play Psychological Stress RNA Research Research Personnel Role Signal Pathway Signal Transduction Small Interfering RNA Stress Symptoms TNF gene Technology Testing Therapeutic Tight Junctions Tissues United States National Institutes of Health Up-Regulation Work afferent nerve base biological adaptation to stress design innovation mast cell neuroregulation novel prevent protective effect public health relevance relating to nervous system therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the mechanisms by which psychological stress triggers defects in intestinal epithelial barrier function. Previous work has demonstrated that corticotropin releasing factor (CRF), a small peptide released from the hypothalamus and intestinal tissues during the stress response, triggers the breakdown in intestinal epithelial barrier function through the activation of CRF receptors expressed on the intestinal mast cell. The proposed studies will investigate how neural signaling plays a critical role in the amplification of CRF-mast cell signaling pathways. The project, based on previous studies and recent preliminary data, will test the hypothesis, that neural-mast cell communication induces the up-regulation of mast cell signaling pathways that prime the mast cell for enhanced responsiveness to CRF. Understanding how the nervous system regulates CRF-mast cell signaling pathways is highly relevant to important GI diseases including Irritable Bowel Syndrome (IBS) and the Inflammatory Bowel Diseases (IBDs). In Specific Aim 1, RNA array technology will be utilized in nerve-mast cell co-cultures to identify the mast cell signaling pathways that are up-regulated by neural signaling. In Specific Aim 2, siRNA technology in nerve-mast cell co- cultures will be utilized to confirm the role of neural-mediated signaling pathways in mast cell responsiveness to CRF. These specific aims are designed to significantly advance our fundamental understanding of neuro- immune signaling in stress-induced GI diseases and they will likely reveal novel targets for innovative preventative and therapeutic strategies.

描述（申请人提供）：本研究的长期目标是了解心理压力引发肠上皮屏障功能缺陷的机制。先前的研究表明，促肾上腺皮质激素释放因子（CRF）是一种在应激反应期间从下丘脑和肠道组织释放的小肽，通过激活肠道肥大细胞上表达的 CRF 受体，引发肠上皮屏障功能的破坏。拟议的研究将调查神经信号传导如何在 CRF-肥大细胞信号传导途径的放大中发挥关键作用。该项目基于之前的研究和最近的初步数据，将检验以下假设：神经肥大细胞通讯会诱导肥大细胞信号通路上调，从而增强肥大细胞对 CRF 的反应性。了解神经系统如何调节 CRF 肥大细胞信号通路与重要的胃肠道疾病（包括肠易激综合征 (IBS) 和炎症性肠病 (IBD)）高度相关。在具体目标 1 中，RNA 阵列技术将用于神经肥大细胞共培养，以识别受神经信号传导上调的肥大细胞信号传导途径。在具体目标 2 中，神经肥大细胞共培养中的 siRNA 技术将用于确认神经介导的信号通路在肥大细胞对 CRF 反应中的作用。这些具体目标旨在显着增进我们对应激诱发的胃肠道疾病中神经免疫信号传导的基本理解，并且它们可能会揭示创新预防和治疗策略的新靶点。