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触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）是应激反应中下丘脑和肠道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。拟建的研究将探讨神经信号如何在crf -肥大细胞信号通路的放大中发挥关键作用。该项目基于先前的研究和最近的初步数据，将测试假设，即神经-肥大细胞通讯诱导肥大细胞信号通路上调，使肥大细胞增强对CRF的反应。了解神经系统如何调节crf -肥大细胞信号通路与肠易激综合征（IBS）和炎症性肠病（IBDs）等重要胃肠道疾病高度相关。在Specific Aim 1中，RNA阵列技术将用于神经-肥大细胞共培养，以鉴定受神经信号上调的肥大细胞信号通路。在Specific Aim 2中，神经肥大细胞共培养中的siRNA技术将被用于确认神经介导的信号通路在肥大细胞对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性胃肠道疾病中神经免疫信号的基本理解，并可能为创新的预防和治疗策略揭示新的靶点。

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.