Central TRPV1 in Cardiovascular Regulation

描述（由申请人提供）：瞬时受体电位香草样1型受体（TRPV1）有助于检测毒热（>420C）和脊髓初级传入伤害感受器的组织损伤。本研究将探讨TRPV1在颅初级传入事件中的表达如何控制新近发现的突触传递形式——TRPV1介导的非同步谷氨酸传递的机制。我们的初步研究表明，这种TRPV1机制在生理温度下是活跃的，并以传入活动依赖的方式增强持久的谷氨酸释放-后者是突触可塑性的一种新形式。这种谷氨酸传递的新形式只存在于辣椒素敏感的孤立束传入的传递中。本研究计划拟建立TRPV1在ST传入传递中的作用机制，重点研究CNS在心血管控制中的功能。我们的整体假设提出，定位于突触前颅传入终端的TRPV1是NTS中多个信号的焦点积分器。在这一关键作用中，我们假设TRPV1作为增益变阻器-增加或减少无髓鞘压力感受器传入的影响。我们将研究TRPV1在NTS中结合温度相关信号的作用；g蛋白偶联受体、膜源性脂质介质等信号。初步研究表明，兴奋性谷氨酸囊泡的异步TRPV1库独立于负责传入动作电位在低抖动潜伏期触发的兴奋性突触后电流的同步谷氨酸囊泡库，这一同步释放过程在所有孤立束传入事件中似乎是相同的。我的实验室在TRPV1在外周压力感受器、压力感受器反射和中枢ST传递机制方面有丰富的经验。研究将依靠包括电生理、活细胞成像、染料追踪和大鼠、小鼠和转基因小鼠相结合的反射测定等方法。我们的具体目标包括评估大麻素信号在传入活动依赖的异步谷氨酸释放产生中的作用，蛋白激酶C的需求，g蛋白偶联受体对异步释放敏化的贡献，以及NTS TRPV1对心血管调节的影响。该研究将帮助我们充分了解这些神经控制机制的正常基础，以便确定临床综合征的病理生理变化和新的治疗途径，这些综合征可能包括中枢神经系统炎症、高血压、中风、代谢综合征和心力衰竭的后果——所有这些都显示出改变的自主神经反射对有害的影响。

DESCRIPTION (provided by applicant): Transient Receptor Potential Vanilloid Type 1 Receptors (TRPV1) contribute to detection of noxious heat (>420C) and tissue damage by spinal primary afferent nociceptors. This proposal will examine the mechanisms by which TRPV1 expression in cranial primary afferents within the solitary tract nucleus (NTS) control a newly discovered form of synaptic transmission - TRPV1 mediated asynchronous glutamate transmission. Our Preliminary Studies indicate that this TRPV1 mechanism is active at physiological temperatures and potentiates long-lasting glutamate release in an afferent activity-dependent fashion - the latter being a new form of synaptic plasticity. This new form of glutamate transmission is only present in transmission from capsaicin sensitive solitary tract afferents. The Research Plan proposes to establish the mechanisms of action of TRPV1 in ST afferent transmission with a focus on CNS function in cardiovascular control. Our global hypothesis proposes that TRPV1 localized to presynaptic cranial afferent terminals is a focal integrator of multiple signals in NTS. In this pivotal role, we postulate that TRPV1 serves as a gain rheostat - increasing or decreasing the impact of unmyelinated baroreceptor afferents. We will investigate the role of TRPV1 in NTS in combining signals related to temperature; G-protein coupled receptors, membrane derived lipid mediators and other signals. Preliminary work indicates that the asynchronous TRPV1 pool of excitatory glutamate vesicles is regulated independently from the synchronous glutamate vesicle pool responsible for excitatory postsynaptic currents triggered at low jitter latency by afferent action potentials - a synchronous release process that appears identical in all solitary tract afferents. My laboratory has extensive experience with TRPV1 mechanisms in peripheral baroreceptors, baroreceptor reflexes, and central ST transmission. Studies will rely on methods including electrophysiological, live cell imaging, dye tracing and reflex assays in a combination of rats, mice and transgenic mice. Our Specific Aims include evaluations of cannabinoid signaling in afferent activity-dependent generation of asynchronous glutamate release, protein kinase C requirements, G-protein coupled receptor contributions to sensitizing asynchronous release, and NTS TRPV1 impact on cardiovascular regulation. The proposed research will help us to fully understand the normal basis of these neural control mechanisms in order to identify pathophysiological changes and new therapeutic avenues in clinical syndromes that may include consequences of central nervous system inflammation, hypertension, stroke, metabolic syndrome, and heart failure - all of which display altered autonomic reflexes to detrimental effect.