Signaling pathways regulating mechanoreflex sensitization in cardiovascular disease

项目总结 许多形式的心血管疾病的显著特征包括运动不耐受和 遭受不良的缺血性心血管事件，如心脏颤动、心肌梗死或中风 在体力消耗时。运动期间交感神经系统活动的夸大增加(即， 交感神经兴奋)是导致运动不耐受和此类不良事件风险的直接因素。在.期间 运动，与收缩骨骼肌相关的机械力刺激小直径肌肉 感觉神经元(III/IV组肌肉传入)，在反射的激活中起着不可或缺的作用， 运动升压反射，在运动过程中有助于增加交感神经系统的活动。这个 这个项目的目标是研究导致机械性夸大的细胞信号机制。 心血管疾病中激活的运动加压反射交感神经控制信号。具体地说，我们将使用 股动脉慢性结扎的大鼠肢体缺血模型(模拟外周动脉模型 动脉疾病)，以及分子和全动物方法的补充混合方法来研究 肌肉感觉神经元内的信号通路，导致病理生理增强 机械激活的通道功能。融合了多种实验技术，包括 分子、电生理学、反射和有意识运动实验将确保我们的发现是可靠的， 综合性的，翻译性的。在目标1中，我们将研究肌醇1，4，5-三磷酸所起的作用 夸大机械损伤后III/IV组肌肉传入中的(IP3)受体和钙信号的改变 慢性肢体缺血大鼠运动加压反射(即机械反射)的组成部分。在目标2中， 我们将研究cAMP激活的交换蛋白(EPAC)，特别是EPAC 1在信号转导中所起的作用 在III/IV组，肌肉传入参与了慢性肢体缺血大鼠机械反射的夸大。在《目标3》中， 我们将研究蛋白激酶C，特别是蛋白激酶Cε在第III/IV组肌肉中的信号转导作用 慢性肢体缺血大鼠夸大机械反射的传入。这个项目具有创新性，因为 这是第一个系统地研究机械地调节细胞功能的信号机制。 在心血管疾病的运动中，激活的有助于交感神经兴奋的通道。这个项目 具有重要意义，因为实验可能确定三个新的靶点(IP3受体、EPAC1和PKCε) 旨在减轻交感神经兴奋、运动不耐受和/或增加缺血性事件风险的治疗 在心血管疾病患者中。

PROJECT SUMMARY Hallmark features of many forms of cardiovascular disease include exercise intolerance and a high risk of suffering an adverse ischemic cardiovascular event such as cardiac fibrillation, myocardial infarction, or stroke during physical exertion. An exaggerated increase in sympathetic nervous system activity during exercise (i.e., sympathoexcitation) is a direct contributor to exercise intolerance and the risk of such adverse events. During exercise, mechanical forces associated with contracting skeletal muscles stimulate small diameter muscle sensory neurons (group III/IV muscle afferents) which plays an integral role in the activation of a reflex, the exercise pressor reflex, that contributes to increased sympathetic nervous system activity during exercise. The goal of this project is to investigate the cellular signaling mechanisms that result in exaggerated mechanically- activated exercise pressor reflex sympathetic control signals in cardiovascular disease. Specifically, we will use a rat model of limb ischemia in which a femoral artery is chronically ligated (a model of simulated peripheral artery disease) and a complementary blend of molecular and whole-animal approaches to investigate the signaling pathways within muscle sensory neurons that result in a pathophysiological enhancement of mechanically-activated channel function. The incorporation of multiple experimental techniques including molecular, electrophysiology, reflex, and conscious exercise experiments will ensure that our findings are robust, integrative, and translational in nature. In Aim 1, we will investigate the role played by inositol 1,4,5-trisphosphate (IP3) receptors and altered calcium signaling in group III/IV muscle afferents in the exaggerated mechanical component of the exercise pressor reflex (i.e., the mechanoreflex) in rats with chronic limb ischemia. In Aim 2, we will investigate the role played by exchange protein activated by cAMP (EPAC), especially EPAC 1, signaling in group III/IV muscle afferents in the exaggerated mechanoreflex in rats with chronic limb ischemia. In Aim 3, we will investigate the role played by protein kinase C (PKC), especially PKCε, signaling in group III/IV muscle afferents in the exaggerated mechanoreflex in rats with chronic limb ischemia. This project is innovative because it is the first to systematically investigate the signaling mechanisms that modulate the function of mechanically activated channels that contribute to sympathoexcitation during exercise in cardiovascular disease. This project is significant because the experiments may identity three novel targets (IP3 receptors, EPAC1, and PKCε) for therapies aimed at mitigating sympathoexcitation, exercise intolerance, and/or elevated risk of ischemic events in cardiovascular disease patients.