Vascular Mechanosensor

描述（由申请人提供）：我实验室的长期目标是了解机械转导的分子基础。这包括1)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组分的鉴定，2)物理和激素因素对机械敏感离子通道表达的调节，以及3)参与心血管病理生理（高血压、自主神经功能障碍）。目前的提案将解决一个高度新颖的研究领域：ENaC蛋白在血管平滑肌中作为机械传感器的作用。高血压引起的肾损伤有多种原因，包括激素、自分泌因素和压力。压力诱导或肌源性肾血管收缩可保护肾脏免受压力相关损伤。压力刺激机械转导的分子机制尚不清楚。这一提议的假设基础是β和/或γ ENaC蛋白是血管平滑肌细胞中机械敏感离子通道复合物的组成部分。压力诱导的血管张力激活含有β和γ ENaC的机械敏感通道，导致钠和钙流入和肌源性收缩。由于肌原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原性收缩并使肾脏容易受到压力性损伤。本研究的目的是确定β ENaC蛋白在以下几个方面是否必需：1)肌原性收缩；2)压力激活的钠离子和钙离子瞬态；3)肾脏自动调节；4)肾保护免受压力性损伤，肾叶间动脉段。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的方式沉默。这一建议的结果将有助于确定肌原性收缩的分子机制，并提供更好地理解压力诱导的末端器官损伤。

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.