RET Ligand Regulation of Intestinal Motility

描述（由申请人提供）：肠神经系统（ENS）是肠壁内由神经元和胶质细胞组成的复杂网络，对正常肠道功能至关重要。当ENS发育异常时，会出现严重的肠道运动问题，包括先天性巨结肠病（远端肠神经节病）和假性肠梗阻。较不严重但更常见的ENS结构或功能问题也可能导致许多肠易激综合征病例。Ret酪氨酸激酶信号的缺陷是Hirschsprung病最常见的原因，并可能导致ENS结构和功能的各种异常。Ret信号对于ENS前体存活、增殖、迁移和轴突延伸至关重要。此外，Ret激活在体内和体外都影响神经元活动。模型细胞培养系统的研究已经确定了许多由Ret激活的细胞内信号通路。尽管取得了这些进展，但仍存在许多问题。特异性Ret信号通路对ENS发展的重要性尚不清楚，影响Ret突变人群Hirschsprung病外显率的因素也知之甚少。我将利用大量小鼠突变来确定特异性Ret信号通路对ENS体内发育的重要性。Specific Aim II将使用原代培养的ENS前体来评估这些相同信号通路的重要性。这些研究将定义特异性Ret激活信号系统如何影响ENS前体存活、增殖、迁移和轴突延伸。具体目标III将确定为什么维生素A信号对ENS的发展很重要，并确定类维生素A和Ret信号之间的相互作用。所有提出的实验都旨在提供ENS发展机制的更详细信息，从而可能导致人类运动障碍的新治疗策略。

DESCRIPTION (provided by applicant): The enteric nervous system (ENS) is a complex network of neurons and glia within the bowel wall that is essential for normal intestinal function. When ENS development is abnormal, serious problems with intestinal motility occur, including Hirschsprung's disease (distal intestinal aganglionosis) and intestinal pseudo-obstruction. Less severe, but more common problems with ENS structure or function may also contribute to many cases of irritable bowel syndrome. Defects in Ret tyrosine kinase signaling are the most common cause of Hirschsprung's disease and may result in a wide variety of abnormalities in ENS structure and function. Ret signaling is essential for ENS precursor survival, proliferation, migration, and axon extension. In addition, Ret activation influences neuronal activity both in vitro and in vivo. Studies in model cell culture systems have identified many intracellular signaling pathways activated by Ret. Despite these advances, many questions remain. The importance of specific Ret signaling pathways for ENS development is not yet known and factors that influence the penetrance of Hirschsprung's disease in people with Ret mutations are poorly understood. Specific Aim I will take advantage of a large number of mouse mutations to determine the importance of specific Ret signaling pathways for ENS development in vivo. Specific Aim II will evaluate the importance of these same signaling pathways using ENS precursors grown in primary culture. These studies will define how specific Ret activated signaling systems influence ENS precursor survival, proliferation, migration and axon extension. Specific Aim III will determine why vitamin A signaling is important for ENS development and identify interactions between retinoid and Ret signaling. All of the proposed experiments are designed to provide more detailed information about mechanisms of ENS development that may lead to novel treatment strategies for human motility disorders.