Vascular Mechanosensor

血管机械传感器

• 批准号: 7463616
• 负责人: Heather A Drummond
• 金额: $ 37万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-06 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463616
• 关键词: Acute; Address; Afferent Neurons; Albuminuria; Area; Arteries; Autonomic Dysfunction; Blood Pressure; Blood Vessels; Calcium; Calcium ion; Cardiovascular system; Chronic; Complex; Constriction procedure; Data; Dominant-Negative Mutation; Fluorescence; Functional disorder; Goals; Homeostasis; Hormonal; Hypertension; Injury; Interlobar; Ion Channel; Ions; Kidney; Mechanics; Molecular; Mus; Muscle Cells; Muscle Contraction; Organ; Perfusion; Proteins; Regulation; Renal Blood Flow; Research; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Sodium; Stimulus; Stretching; Techniques; Testing; Time; Tissues; Transgenic Model; Transgenic Organisms; Vascular Smooth Muscle; Work; autocrine; base; epithelial Na+ channel; gamma ENaC; glomerulosclerosis; kidney vascular structure; mouse model; novel; pressure; prevent; response; vasoconstriction

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.

描述（由申请人提供）：我实验室的长期目标是了解力转导的分子基础。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成分的鉴定，2) 物理和激素因素对机械敏感离子通道表达的调节，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高度新颖的研究领域：ENaC 蛋白作为血管平滑肌机械传感器的作用。高血压引起的肾损伤有多种原因，包括激素和自分泌因素以及压力。压力引起的或肌源性的肾血管收缩可以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尚不清楚。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离子通道复合物的组成部分。压力引起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。由于肌源性收缩可以保护肾脏免受终末器官损伤，因此我们进一步假设β ENaC 表达的丧失将阻止肌源性收缩并使肾脏易于受到压力诱导的损伤。该提案的目标是确定 1) 肌源性收缩、2) 压力激活钠离子和钙离子瞬变、3) 肾脏自动调节和 4) 肾脏保护免受压力诱导损伤、肾叶间动脉段是否需要 β ENaC 蛋白。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。该提案的结果将有助于定义肌源性收缩的分子机制，并提供对压力引起的终末器官损伤的更好理解。