Neural Priming of CRF-Mast Cell Signaling

描述（由申请人提供）：本研究的长期目标是了解心理应激引发肠上皮屏障功能缺陷的机制。促肾上腺皮质激素释放因子（corticotropin releasing factor，CRF）是应激反应时下丘脑和肠组织释放的一种小肽，通过激活肠肥大细胞上表达的CRF受体，触发肠上皮屏障功能的破坏。拟议的研究将探讨神经信号传导如何在CRF-肥大细胞信号传导通路的放大中发挥关键作用。该项目，基于以前的研究和最近的初步数据，将测试假设，即神经肥大细胞通信诱导肥大细胞信号通路的上调，该通路使肥大细胞对CRF的反应性增强。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高度相关，包括肠易激综合征（IBS）和炎症性肠病（IBD）。在特定目标1中，RNA阵列技术将用于神经-肥大细胞共培养物中，以鉴定由神经信号传导上调的肥大细胞信号传导途径。在特定目标2中，将利用神经-肥大细胞共培养物中的siRNA技术来确认神经介导的信号传导途径在肥大细胞对CRF的反应性中的作用。这些特定目标旨在显著推进我们对应激诱导的GI疾病中神经免疫信号传导的基本理解，并且它们可能揭示创新预防和治疗策略的新靶点。

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.