BDNF and the Exercise Pressor Reflex in Heart Fail.ure

 描述(申请人提供)：慢性心力衰竭(CHF)是美国主要的死亡原因之一。这种疾病的一个主要特征是在体力活动中交感神经兴奋和运动耐量增加。在心力衰竭患者的运动中，交感神经系统的极端激活经常被看到，并引起伴随着过度换气的夸大的升压反应。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。实验证据表明：(1)运动中交感神经兴奋的夸大与运动加压反射(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)的增强是CHF EPR增大的主要原因。CHF机械敏感型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(特别是脑源性神经营养因子)在CHF时EPR机械传入肢体的敏化中起关键作用。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。由于充血性心力衰竭时骨骼肌灌流不足，会有活性氧物质的释放和炎症反应。这些传入终末的应激可能刺激腰背根神经节(DRGs)的肌肉传入神经元产生神经营养因子以维持生存。然而，BDNF的作用与其神经营养特性无关，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。我们将使用分子(实时聚合酶链式反应、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、单一传入记录)等高度集成的技术来验证BDNF假说。我们相信，这项拟议的研究将解决与充血性心力衰竭患者生活质量直接相关的重要功能和机制问题。这些数据将揭示这一患者群体中治疗的新靶点。

 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.