Neural Priming of CRF-Mast Cell Signaling

描述(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(CRF)是应激反应过程中从下丘脑和肠道组织释放的一种小肽，它通过激活肠道肥大细胞上表达的CRF受体来触发肠上皮屏障功能的破坏。这项拟议的研究将调查神经信号如何在CRF-肥大细胞信号通路的扩增中发挥关键作用。该项目基于之前的研究和最近的初步数据，将检验这一假设，即神经-肥大细胞通讯诱导肥大细胞信号通路上调，从而使肥大细胞对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包括肠易激综合征(IBS)和炎症性肠病(IBDS)在内的重要胃肠道疾病高度相关。在具体目标1中，RNA阵列技术将用于神经-肥大细胞共培养，以确定神经信号上调的肥大细胞信号通路。在具体目标2中，将利用神经-肥大细胞共培养中的siRNA技术来证实神经介导的信号通路在肥大细胞对CRF的反应中所起的作用。这些特定的目的旨在显著提高我们对应激诱导的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.