BDNF and the Exercise Pressor Reflex in Heart Fail.ure

BDNF 和心力衰竭中的运动加压反射

基本信息

批准号：
9256530
负责人：
Hanjun Wang
金额：
$ 37.63万
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：
2016
资助国家：
美国
起止时间：
2016-04-06 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256530
关键词：
Acute Address Afferent Neurons American Animal Experiments Animals Brain Brain-Derived Neurotrophic Factor Cardiovascular Abnormalities Cardiovascular Physiology Cardiovascular system Cause of Death Characteristics Clinical Research Congestive Heart Failure Data Deterioration Disease Down-Regulation Environmental air flow Exercise Exercise Tolerance Exhibits Fiber Functional disorder Ganglia Gated Ion Channel Goals Heart Heart Rate Heart failure Human Hyperventilation Immunofluorescence Immunologic Inflammation Ion Channel Gating Isometric Exercise Limb structure Measures Mechanics Mediating Membrane Potentials Metabolic Mitogen-Activated Protein Kinases Molecular Muscle Muscle Contraction Nerve Nerve Endings Nerve Growth Factors Neuraxis Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Patients Peripheral Phosphotransferases Physical activity Physiological Play Potassium Potassium Channel Production Property Rattus Reactive Oxygen Species Reflex action Regulation Research Rest Role Sensory Signal Pathway Skeletal Muscle Spinal Ganglia Stress Sympathetic Nervous System Techniques Testing Time Transfection Tropomyosin Up-Regulation Viral Western Blotting afferent nerve arm base cardiovascular risk factor electrical property exercise capacity exercise intolerance exercise training experimental study neuronal cell body neuronal excitability neuroregulation neurotropic new therapeutic target novel patch clamp patient population pressure prevent public health relevance respiratory response therapy development 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 primary characteristic of this disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise pressor reflex (EPR); and 2) the enhanced mechanically sensitive afferent component of this reflex (i.e. mechanoreflex) primarily contributes to the exaggerated EPR in CHF. The molecular and cellular mechanisms underlying the selective sensitization of the mechano-sensitive afferent limb in CHF has not fully understood. Here, we propose to test a novel hypothesis that neurotrophins (especially brain-derived neurotrophic factor, BDNF) in muscle afferent neurons play a critical role in the sensitization of the mechanical afferent limb of the EPR in CHF. We believe that this pathway operates by a mitogen-activated protein kinase (MAPK)-K+ channel mechanism. Due to underperfusion of skeletal muscle in CHF there is release of reactive oxygen species and inflammation. These stress in afferent terminal endings may stimulate muscle afferent neurons in lumbar dorsal root ganglia (DRGs) to generate neurotrophins for survival. However, effects of BDNF separate from its neurotrophic properties may also increase neuronal excitability and terminal sensitivity by activating MAPK pathways and modulating the electrical properties of voltage-gated ion channels such as K+ channels. We will use highly integrative techniques including molecular (real-time PCR, western blot, immunofluorescence and viral transfection), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test the BDNF hypothesis in this project. We believe that this proposed research will address important functional and mechanistic issues that directly relate to the quality of lif in patients with CHF. These data will uncover new targets for therapy in this patient population.

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。这种疾病的主要特征是心力衰竭患者在运动过程中交感兴奋和运动不耐受性升高。交感神经系统的激活经常出现，并引起过度的升压反应，并伴有过度换气。实验证据表明，这些异常可能会增加这些患者在体力活动期间的心血管风险。运动期间过度的交感兴奋与运动加压反射 (EPR) 的敏感性增加直接相关；2) 这种反射的机械敏感传入成分（即机械感受反射）主要导致 CHF 细胞机制中 EPR 的过度增加。 CHF 中机械敏感传入肢的选择性敏化尚未完全了解，在此，我们建议检验神经营养素（尤其是神经营养素）的新假设。肌肉传入神经元中的脑源性神经营养因子 (BDNF) 在 CHF 中 EPR 机械传入肢的敏化中发挥着关键作用，我们认为该途径通过丝裂原激活蛋白激酶 (MAPK)-K+ 通道机制发挥作用。由于 CHF 中骨骼肌灌注不足，会释放活性氧和炎症，这些传入末梢的压力可能会刺激腰椎背根的肌肉传入神经元。然而，BDNF 与其神经营养特性无关的作用也可能通过激活 MAPK 通路和调节电压门控离子通道（如 K+ 通道）的电特性来增加神经元兴奋性和终末敏感性。使用高度集成的技术，包括分子（实时 PCR、蛋白质印迹、免疫荧光和病毒转染）、细胞（膜片钳）和整体动物实验（测量 EPR 功能、单我们相信，这项拟议的研究将解决与 CHF 患者的生活质量直接相关的重要功能和机制问题。这些数据将揭示该患者群体的治疗新目标。。