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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：
8573798
负责人：
Irving H Zucker
金额：
$ 44.77万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8573798
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 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 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）是美国死亡的主要原因之一，CHF患者的标志是在体育活动期间交感神经兴奋升高和运动不耐受。即使在适度的运动中，交感神经系统的极度激活也经常导致过度的压力反应和过度通气，这可能会增加这些人在体育活动中患心血管疾病的风险