BDNF and the Exercise Pressor Reflex in Heart Fail.ure

BDNF 和心力衰竭中的运动加压反射

• 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
• 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

 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）是美国的主要死因之一。这种疾病的主要特征是在体力活动期间交感神经兴奋和运动不耐受升高。在心力衰竭患者的运动过程中，经常可以看到交感神经系统的极度激活，并引起过度的升压反应，伴随着过度通气。这些异常可能会增加这些患者体力活动期间的心血管风险。实验证据表明：1）运动期间过度的交感神经兴奋与运动加压反射（EPR）的敏感性增加直接相关; 2）该反射的机械敏感传入成分（即机械反射）的增强主要导致CHF中过度的EPR。CHF中机械敏感传入肢体选择性敏化的分子和细胞机制尚未完全了解。在这里，我们提出了一个新的假设，即肌肉传入神经元中的神经营养因子（尤其是脑源性神经营养因子，BDNF）在CHF中EPR的机械传入肢体的敏化中起着关键作用。我们认为，这一途径是通过丝裂原活化蛋白激酶（MAPK）-K+通道机制进行的。由于CHF中骨骼肌灌注不足，存在活性氧自由基和炎症的释放。这些传入终末的应激可能刺激腰背根神经节（DRG）中的肌肉传入神经元产生神经营养因子以维持生存。然而，BDNF与其神经营养特性分离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的兴奋性和终末敏感性。我们将使用高度整合的技术，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，单传入记录）来验证BDNF假说。我们相信这项研究将解决与CHF患者生活质量直接相关的重要功能和机制问题。这些数据将揭示该患者人群的新治疗靶点。