Signaling pathways regulating mechanoreflex sensitization in cardiovascular disease

调节心血管疾病中机械感受反射敏化的信号通路

• 批准号: 10641947
• 负责人: Steven W Copp
• 金额: $ 52.06万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641947
• 关键词: Adverse event; Afferent Neurons; Animal Experiments; Animals; Biological; Blood Pressure; Calcium; Calcium Signaling; Cardiac; Cardiovascular Diseases; Cardiovascular system; Chronic; Conscious; Contracts; Cyclic AMP; Data; Development; Diameter; Disease; Electrophysiology (science); Ensure; Event; Exercise; Exertion; Feedback; Goals; Health; Heart; Hindlimb; Hour; Hypersensitivity; Inflammatory; Inositol; Investigation; Ischemia; Laboratories; Ligation; Literature; Mechanics; Modeling; Molecular; Muscle; Myocardial Infarction; Nature; Nerve; Oxygen; Patients; Peripheral; Peripheral arterial disease; Phosphorylation; Play; Population Group; Pre-Clinical Model; Protein Kinase C; Proteins; Publications; Rattus; Receptor Signaling; Reflex action; Reflex control; Risk; Role; Sensory; Signal Pathway; Signal Transduction; Skeletal Muscle; Stress; Stroke; Sympathetic Nervous System; Techniques; Testing; Tissues; coronary vasoconstriction; exercise capacity; exercise intolerance; experimental study; femoral artery; high risk; innovation; inorganic phosphate; insight; limb ischemia; mechanical force; mechanotransduction; novel; pain model; pain signal; receptor

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.

项目摘要 许多形式的心血管疾病的标志性特征包括运动不耐受和高风险的心血管疾病。 患有不良缺血性心血管事件，如心脏纤维性颤动、心肌梗死或中风 在体力消耗中。运动期间交感神经系统活动过度增加（即， 交感神经兴奋）是运动不耐受和此类不良事件风险的直接促成因素。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）在反射激活中起着不可或缺的作用， 运动加压反射，运动时有助于增加交感神经系统活动。的 这个项目的目的是研究细胞信号机制，导致夸大的机械- 激活运动升压反射交感神经控制信号在心血管疾病中的作用。具体来说，我们将使用 其中股动脉被慢性结扎的肢体缺血的大鼠模型（模拟外周血管缺血的模型）， 动脉疾病）和分子和整体动物方法的互补混合，以研究 肌肉感觉神经元内的信号传导通路，导致 机械激活通道功能。多种实验技术的结合，包括 分子、电生理学、反射和意识运动实验将确保我们的发现是可靠的， 综合性和翻译性。在目标1中，我们将研究肌醇1，4，5-三磷酸 (IP3)受体和改变的钙信号在III/IV组肌肉传入在夸张的机械 运动加压反射的分量（即，机械反射）。在目标2中， 我们将研究由cAMP激活的交换蛋白（EPAC），特别是EPAC 1， III/IV组肌传入纤维在慢性肢体缺血大鼠的过度机械反射中的作用。在目标3中， 我们将研究蛋白激酶C（PKC），特别是PKCε，在III/IV组肌肉中的作用 慢性肢体缺血大鼠过度机械反射中的传入纤维该项目具有创新性，因为 这是第一个系统地研究信号机制，调节功能的机械 在心血管疾病的运动过程中有助于交感神经兴奋的激活通道。这个项目 是重要的，因为实验可以确定三个新的目标（IP 3受体，EPAC 1和PKCε）， 旨在减轻交感神经兴奋、运动不耐受和/或缺血性事件风险升高的治疗 心血管疾病患者。