MECHANOTRANSDUCTION IN INTESTINAL SMOOTH MUSCLE CELLS

机械门控离子通道为细胞提供了一种响应机制 直接影响到他们的环境变化，并参与了几个 关键的细胞功能，包括细胞分裂，调节体积， 肌肉张力和肌肉肥大。心脏和血管神经元 平滑肌细胞具有机械门控离子通道。但 机械门控离子通道的存在和意义 胃肠平滑肌是未知的。的目的 建议是建立机械门控的生理重要性 人和犬空肠环形平滑肌的离子通道 细胞PI获得的初步数据表明，膜 拉伸、细胞体积增加和细胞骨架操纵 调节人和犬空肠环的全细胞电流 平滑肌细胞根据这些初步数据， 该建议的假设是机械门控离子通道是 存在于平滑肌细胞上， 最终导致离子通量和膜电位的变化 导致肠收缩力的变化。有三 具体目标：（1）确定人体形状或大小的变化 犬空肠环形平滑肌细胞激活机械门控 （2）确定哪一个或哪些离子通道是离子通道的基础; 细胞大小变化引起的全细胞电流增加，或 形状;和（3），以确定是否调节机械门控离子通道 开放概率取决于细胞骨架。的 开发用于获得健康人的分离技术 小肠平滑肌细胞的PI将使使用 膜片钳记录和免疫荧光技术，以解决 三个具体目标。机械门控离子通道的演示 将提供一种新的途径， 小肠平滑肌细胞可以直接适当地 应对环境的变化。机械门控激活 离子通道在平滑肌中可能具有生理学意义 对正常消化中腔内压力变化的反应，以及 炎症或阻塞性疾病的病理生理学意义 克罗恩病、狭窄和肠易激综合征等疾病 机械门控离子通道可能过度表达的综合征。

Mechano-gated ion channels provide a mechanism for cells to respond directly to changes in their environment and are involved in several key cellular functions including cell division, regulation of volume, muscle tone and muscle.hypertrophy. Neurons, cardiac, and vascular smooth muscle cells have mechano-gated ion channels. However, the presence and significance of mechano-gated ion channels in gastrointestinal smooth muscle is unknown. The objective of this proposal is to establish the physiological importance of mechano-gated ion channels in single human and canine jejunal circular smooth muscle cells. The Preliminary data obtained by the PI suggest that membrane stretch, increase in cell volume, and cytoskeletal manipulation modulate the whole cell current in human and canine jejunal circular smooth muscle cells. Based on these preliminary data the working hypothesis of this proposal is that mechano-gated ion channels are present on smooth muscle cells and that activation of the channels results in changes in ionic flux and membrane potential, ultimately resulting in changes in intestinal contractility. There are three specific aims: (1) to determine if a change in shape or size of human and canine jejunal circular smooth muscle cells activates mechano-gated channels; (2) to determine which ion channel or channels underlies the increase in whole cell current evoked by a change in cell size or shape; and (3), to determine if regulation of mechano-gated ion channel open probability is dependent on the cellular cytoskeleton. The development of a dissociation technique for obtaining healthy human small intestinal smooth muscle cells by the PI will enable the use of patch clamp recordings and immunofluorescent techniques to address the three specific aims. The demonstration of mechano-gated ion channels in gastrointestinal smooth muscle will provide a novel pathway by which small intestinal smooth muscle cells can directly and appropriately respond to changes in their environment. Activation of mechano-gated ion channels may be of physiological significance in the smooth muscle response to changes in intraluminal pressure in normal digestion, and of pathophysiological significance in inflammatory or obstructive diseases such as Crohn's disease and strictures and in irritable bowel syndrome where mechano-gated ion channels may be overexpressed.