Molecular and Cellular Determinants of the Exercise Pressor Reflex in CHF

CHF 运动加压反射的分子和细胞决定因素

基本信息

批准号：
8896857
负责人：
Irving H Zucker
金额：
$ 45.54万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896857
关键词：
Acute Address Affect Afferent Neurons American Animal Experiments Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Area Attenuated Cardiovascular Physiology Cardiovascular system Cause of Death Cells Chronic Clinical Research Congestive Heart Failure Data Deterioration Disease Environmental air flow Exercise Exercise Tolerance Functional disorder Gated Ion Channel Gene Transfer Generations Heart Rate Heart failure Human Hyperventilation Immunofluorescence Immunologic Inflammation Laboratories Measures Mechanics Mediating Microinjections Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Moderate Exercise Molecular Muscle Myocardial Infarction Nerve Neuraxis Neurons Oxidative Stress Oxygen Pathway interactions Patients Peripheral Physical activity Play Process Quality of life Rattus Reactive Oxygen Species Reflex action Regulation Research Rest Role Signal Pathway Skeletal Muscle Sodium Channel Spinal Ganglia Stress Sympathetic Nervous System Techniques Testing Tetrodotoxin Time Training Up-Regulation Western Blotting Work arm base cardiovascular risk factor channel blockers electrical property ganglion cell in vivo neuronal cell body neuronal excitability neuroregulation novel patch clamp pressure prevent public health relevance relating to nervous system research study respiratory response targeted treatment voltage

项目摘要

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A hallmark of CHF patients is elevated sympatho-excitation and exercise intolerance during physical activity. Even during moderate exercise, extreme activation of the sympathetic nervous system is often seen causing an exaggerated pressor response and hyperventilation, which potentially increases cardiovascular risk during physical activity in these patients. Existing evidence indicates that the exaggerated sympatho-excitation during exercise is directly related to increased contribution of the exercise pressor reflex (EPR). However, the molecular and cellular mechanisms underlying the increased EPR in CHF remain to be determined. Due to underperfused areas of skeletal muscle in CHF, release of reactive oxygen species and inflammation may activate the mitogen-activated protein kinase (MAPK) pathways in muscle afferent neurons. We hypothesize that chronic oxidative stress in muscle afferent terminals initiate activation of the MAPK signaling pathway in muscle afferent neurons in CHF. This activation, in turn, increases the afferent input of the EPR by affecting afferent neuronal excitability. At the cellular level, we hypothesize that enhanced voltage-gated sodium channel (Nav) activity in muscle afferent neurons (DRG's) of CHF rats contributes to the enhanced afferent neuronal excitability and the EPR. Since exercise training (ExT) prevents the exaggerated EPR in a myocardial infarction rat model we propose that ExT prevents the exaggerated EPR, in part, by inhibition of excessive activation of the MAPK pathway. We will use highly integrative techniques including molecular (real-time PCR, single cell real-time PCR, western blot, immunofluorescence, and in vivo gene transfer), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test these hypotheses. We believe that the proposed research will address important functional and mechanistic issues that directly relate to the quality of life in patients with CHF. Furthermore, w believe that these data will uncover new targets for therapy in CHF.

描述（由申请人提供）：慢性心力衰竭 (CHF) 是美国的主要原因之一。CHF 患者的一个特点是体力活动期间交感神经兴奋性升高和运动不耐受。即使在适度的运动中，交感神经系统的极度激活也经常会导致过度的升压反应和过度换气，这可能会增加这些人在体力活动期间的心血管风险。患者。现有证据表明，运动期间过度的交感神经兴奋与运动加压反射（EPR）的贡献增加直接相关。然而，CHF 中 EPR 增加的分子和细胞机制仍有待确定。由于 CHF 骨骼肌区域灌注不足，活性氧的释放和炎症可能会激活肌肉传入神经元中的丝裂原激活蛋白激酶 (MAPK) 通路。我们假设肌肉传入末梢的慢性氧化应激启动 CHF 肌肉传入神经元中 MAPK 信号通路的激活。这种激活反过来又通过影响传入神经元的兴奋性来增加 EPR 的传入输入。在细胞水平上，我们假设 CHF 大鼠肌肉传入神经元 (DRG) 中电压门控钠通道 (Nav) 活性的增强有助于传入神经元兴奋性和 EPR 的增强。由于运动训练（ExT）可以防止心肌梗塞大鼠模型中过度的 EPR，因此我们认为 ExT 可以部分通过抑制 MAPK 通路的过度激活来防止过度的 EPR。我们将使用高度整合的技术，包括分子（实时PCR、单细胞实时PCR、蛋白质印迹、免疫荧光和体内基因转移）、细胞（膜片钳）和整体动物实验（测量EPR功能、单传入记录））来检验这些假设。我们相信，拟议的研究将解决与 CHF 患者生活质量直接相关的重要功能和机制问题。此外，我们相信这些数据将揭示治疗 CHF 的新靶点。