The role of glial cells in the enteric nervous system

描述(申请人提供)：肠道神经系统(Ens)由一个复杂的神经元和神经胶质细胞网络组成，该网络延伸至整个胃肠道。 肠道，对正常的消化功能是必不可少的。在中枢和外周神经系统中，胶质细胞对神经元的正常发育、功能和维持以及髓鞘和血脑屏障等结构的形成都是必不可少的。在ENS中，神经胶质细胞的作用在很大程度上仍不清楚。确定一个细胞群体的作用的一个经典方法是消除它，并分析由此对器官功能的影响。以前的研究 采用这种方法在小鼠模型中去除肠上皮胶质细胞已有报道，肠胶质细胞是维持肠上皮屏障和调节上皮细胞增殖所必需的[4，5]。然而，这些小鼠中的大多数都出现了严重的肠道炎症，众所周知，这会影响屏障功能和上皮细胞的周转[6，7]。我们已经建立了一种小鼠遗传模型，在这种模型中，胶质细胞被一种细胞毒素的诱导表达选择性地消融，导致在7天内整个肠道70%以上的肠神经胶质细胞丢失，而没有任何相关的炎症。这一强大的在体肠道胶质细胞丢失模型现在使我们能够更准确地确定肠胶质细胞在关键上皮功能中的作用，并确定对肠胶质细胞功能至关重要的TH信号通路。在目标1中，我们将使用此模型来定义 在正常、非炎症的肠道中，胶质细胞、上皮细胞和神经元之间的关键相互作用。随着肠神经胶质细胞的生理作用(S)的确定，我们可以开始确定涉及的信号通路。NeuRegin-ErbB信号通路是一个主要的候选通路，它在中枢和外周神经系统中调节神经元和胶质细胞之间的重要相互作用。神经调节蛋白(NRGs)是一个营养因子家族，主要由神经元表达，结合并激活由神经胶质细胞表达的ErbB受体酪氨酸激酶家族。在目标2中，我们将使用肠道神经胶质细胞ErbB信号改变的小鼠模型，并评估其对ENS和关键上皮功能的影响。综上所述，拟议中的研究结果将极大地促进我们对ENS生物学的理解，并对肠神经胶质细胞缺陷如何导致消化系统疾病产生新的见解。

DESCRIPTION (provided by applicant): The enteric nervous system (ENS) consists of an elaborate network of neurons and glial cells that extends the entire length of the gastrointestinal tract and is essential for normal digestive function. In the central and peripheral nervous systems, glia are essential for the normal development, function and maintenance of neurons as well as the elaboration of structures such as myelin and the blood-brain barrier. In the ENS, the role of glial cells remains largely unknown. A classic approach to identifying the role of a cell population is to eliminate it and analyze the resulting effects on organ function. Previous studies taking this approach to ablate enteric glia in mouse models have reported that enteric glia are required for maintenance of the intestinal epithelial barrier and regulation of epithelial cell proliferation [4,5]. However, most of these mice developed significant intestinal inflammation, which is known to affect barrier function and epithelial turnover [6,7]. We have developed a mouse genetic model in which glial cells are selectively ablated by the inducible expression of a cellular toxin, resulting in loss of over 70% of enteric glia throughout the intestine within 7 day without any associated inflammation. This robust in vivo model of enteric glial loss now allows us to more precisely identify the role of enteric glia in key epithelial functions and to define th signaling pathways important for enteric glial function. In Aim 1, we will use this model to define critical interactions between glia, epithelial cells and neurons in the normal, non-inflamed intestine. As the physiologic role(s) of enteric glia are defined, we can begin to identify the signaling pathways involved. A prime candidate is the Neuregulin - ErbB signaling pathway known to mediate important interactions between neurons and glia in the central and peripheral nervous systems. Neuregulins (NRGs) are a family of trophic factors, typically expressed by neurons, which bind and activate the ErbB family of receptor tyrosine kinases expressed by glia. In Aim 2, we will use mouse models in which ErbB signaling in enteric glia is altered, and assess the effects on the ENS and on key epithelial functions. Taken together, findings from the proposed studies will significantly advance our understanding of ENS biology and yield new insights on how enteric glial defects contribute to digestive disease.