Vascular Mechanosensor

描述（由申请人提供）：我实验室的长期目标是了解机械传导的分子基础。这包括1）识别感觉神经元和血管平滑肌细胞中机械敏感离子通道复合物的组分，2）通过物理和激素因素调节机械敏感离子通道表达，3）参与心血管病理生理学（高血压，自主神经功能障碍）。目前的提案将解决一个非常新颖的研究领域：ENaC蛋白作为血管平滑肌中的机械传感器的作用。高血压肾损害的原因是多方面的，包括激素和自分泌因素以及压力。压力诱导的或肌源性的肾血管收缩保护肾脏免受压力相关的损伤。压力刺激的机械转导的分子机制是未知的。该提议的假设是β和/或γ ENaC蛋白是血管平滑肌细胞中机械敏感性离子通道复合物的组分。压力诱导的血管张力激活含有β和γ ENaC的机械敏感性通道，导致钠和钙内流和肌源性收缩。由于肌源性收缩保护肾脏免受终末器官损伤，我们进一步假设β ENaC表达的丧失将阻止肌源性收缩并使肾脏易受压力诱导的损伤。本提案的目的是确定β ENaC蛋白是否是1）肌源性收缩和2）压力激活的钠和钙离子瞬变，3）肾自动调节和4）肾叶间动脉段免受压力诱导损伤的肾保护所必需的。为了评估β ENaC在这些反应中的重要性，我们开发了一种双转基因小鼠模型，其中β ENaC以组织和时间选择性方式沉默。这一建议的结果将有助于确定肌源性收缩的分子机制，并提供了一个更好的理解压力诱导的终末器官损伤。

DESCRIPTION (provided by applicant): The long term objective of my lab is to understand the molecular basis of mechanotransduction. This includes the 1) identification of components of mechanosensitive ion channel complexes in sensory neurons and vascular smooth muscle cells, 2) regulation of mechanosensitive ion channel expression by physical and hormonal factors and 3) involvement in cardiovascular pathophysiology (hypertension, autonomic dysfunction). The current proposal will address a highly novel area of research: role of ENaC proteins as mechanosensors in vascular smooth muscle. Hypertension induced renal injury has multiple causes including hormonal and autocrine factors and pressure. Pressure-induced, or myogenic, constriction of renal vessels protects the kidney from pressure related injury. The molecular mechanism underlying mechanotransduction of the pressure stimulus is unknown. The hypothesis underlying this proposal is that beta and/or gamma ENaC proteins are components of mechanosensitive ion channel complexes in vascular smooth muscle cells. Pressure induced vascular tension activates mechanosensitive channels containing beta and gamma ENaC leading to sodium and calcium influx and myogenic constriction. Since myogenic constriction protects the kidney from end-organ damage, we further hypothesize that loss of beta ENaC expression will prevent myogenic constriction and predispose the kidney to pressure induced injury. The goals of this proposal are to determine if beta ENaC protein is required for 1) myogenic constriction, and 2) pressure activated sodium and calcium ion transients, 3) renal autoregulation, and 4) renal protection from pressure induced injury, renal interlobar artery segments. To assess the importance of beta ENaC in these responses, we have developed a double transgenic mouse model where beta ENaC is silenced in a tissue- and time-selective manner. Results from this proposal will help define the molecular mechanism of myogenic constriction and provide a better understanding of pressure induced end organ damage.