Vascular Mechanosensor

描述(申请人提供)：我的实验室的长期目标是了解机械转导的分子基础。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体的组成，2)物理和激素因素对机械敏感离子通道表达的调节，3)参与心血管病理生理学(高血压、自主神经功能障碍)。目前的提案将涉及一个非常新的研究领域：ENaC蛋白在血管平滑肌中作为机械传感器的作用。高血压肾损害的原因是多方面的，包括激素因素、自分泌因素和压力因素。压力引起的或肌源性的肾血管收缩保护肾脏免受压力相关的损伤。压力刺激机械转导的分子机制尚不清楚。这一假设的基础是，β和/或γENaC蛋白是血管平滑肌细胞机械敏感离子通道复合体的组成部分。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，丢失β-ENaC表达将防止肌源性收缩，并使肾脏容易受到压力诱导的损伤。这项建议的目的是确定1)肌源性收缩是否需要βENaC蛋白，2)压力激活的钠和钙离子瞬变，3)肾脏自动调节，4)压力诱导损伤的肾脏保护，肾叶间动脉节段。为了评估βENaC在这些反应中的重要性，我们开发了一个双转基因小鼠模型，其中βENaC以组织和时间选择性的方式沉默。这一提议的结果将有助于确定肌源性收缩的分子机制，并为更好地理解压力诱导的终末器官损伤提供依据。

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.