The role of glial cells in the enteric nervous system

描述（由申请人提供）：肠神经系统（ENS）由神经元和神经胶质细胞的复杂网络组成，延伸至整个胃肠系统。 消化道和正常的消化功能是必不可少的。在中枢和外周神经系统中，神经胶质对于神经元的正常发育、功能和维持以及髓鞘和血脑屏障等结构的形成至关重要。在ENS中，神经胶质细胞的作用在很大程度上仍然未知。确定细胞群作用的经典方法是消除它并分析对器官功能的影响。以前的研究 在小鼠模型中采用这种方法来消融肠神经胶质已经报道了肠神经胶质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发生了显著的肠道炎症，已知其影响屏障功能和上皮更新[6，7]。我们已经开发了一种小鼠遗传模型，其中通过细胞毒素的诱导表达选择性地消融神经胶质细胞，导致在7天内整个肠道中超过70%的肠神经胶质细胞损失，而没有任何相关的炎症。这种肠神经胶质损失的体内模型现在使我们能够更精确地识别肠神经胶质在关键上皮功能中的作用，并定义对肠神经胶质功能重要的信号通路。在目标1中，我们将使用此模型定义 神经胶质细胞，上皮细胞和神经元之间的关键相互作用在正常的，非炎症的肠道。随着肠神经胶质细胞的生理作用的定义，我们可以开始确定参与的信号通路。主要候选者是已知介导中枢和外周神经系统中神经元和神经胶质之间的重要相互作用的神经调节蛋白- ErbB信号传导途径。神经调节蛋白（NRG）是一个家族的营养因子，通常由神经元表达，其结合并激活神经胶质细胞表达的受体酪氨酸激酶的ErbB家族。在目标2中，我们将使用肠神经胶质细胞中ErbB信号传导改变的小鼠模型，并评估对ENS和关键上皮功能的影响。总之，拟议研究的结果将大大促进我们对ENS生物学的理解，并对肠神经胶质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.