Central TRPV1 in Cardiovascular Regulation

描述(由申请人提供)：瞬时受体潜力香草素1型受体(TRPV1)有助于检测伤害性高温(&gt；420C)和脊髓初级传入伤害性感受器的组织损伤。本研究将探讨TRPV1在孤束核(NTS)内初级传入神经的表达控制一种新发现的突触传递形式--TRPV1介导的异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，并以一种传入活动依赖的方式增强长期的谷氨酸释放-后者是突触可塑性的一种新形式。这种新形式的谷氨酸传递只存在于辣椒素敏感孤束传入的传递中。研究计划建议建立TRPV1在ST传入传递中的作用机制，重点是中枢神经系统在心血管控制中的作用。我们的全球假说认为，定位于突触前颅脑传入终末的TRPV1是NTS中多个信号的焦点整合者。在这一关键作用中，我们假设TRPV1作为一种增益变阻器--增加或减少无髓压力感受器传入的影响。我们将研究TRPV1在NTS中结合与温度相关的信号、G蛋白偶联受体、膜源性脂质介质和其他信号的作用。初步工作表明，兴奋性谷氨酸囊泡的异步TRPV1池独立于同步谷氨酸囊泡池进行调节，同步谷氨酸囊泡池负责由传入动作电位在低抖动潜伏期触发的兴奋性突触后电流--这一同步释放过程在所有孤束传入中似乎是相同的。我的实验室对TRPV1在外周压力感受器、压力感受器反射和中央ST段传导方面的机制有丰富的经验。研究将依赖于电生理、活细胞成像、染料追踪和对大鼠、小鼠和转基因小鼠的反射分析等方法。我们的具体目标包括评估大麻素信号在依赖传入活性的产生异步谷氨酸释放中的作用，蛋白激酶C的需求，G蛋白偶联受体对敏化异步释放的作用，以及NTS TRPV1对心血管调节的影响。拟议的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-所有这些都表现出有害的自主神经反射改变。 与公共健康相关：大脑包含神经元网络，对于在与生命相容的状态下维持正常的身体功能至关重要。这些神经元网络形成反射，包括调节足够的血压以支持全身循环以及适当的呼吸频率。这项建议涉及大脑的一个关键部分，它是正常反射所必需的，它会在心脏、血管和肺中产生无意识的调整，从而提供全身正常的条件。这些神经元有时在研究所任务中的疾病状态下功能异常，如高血压、缺氧、代谢综合征和心力衰竭，本研究旨在了解这些神经元控制功能的细胞机制以及它们与心血管调节的关系。

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. PUBLIC HEALTH RELEVANCE: The brain contains networks of neurons that are essential to maintain normal bodily functions in a state compatible with life. These networks of neurons form reflexes that include regulation for an adequate blood pressure to support the systemic circulation as well as appropriate breathing rates. This proposal concerns a key part of the brain that is required for normal reflexes that produce unconscious adjustments in the heart, blood vessels and lungs that provide normal conditions throughout the body. These neurons sometimes function abnormally during disease states within the institute mission such as hypertension, hypoxia, metabolic syndrome, and heart failure, and this research is designed to understand the cellular mechanisms controlling function of these neurons and how they relate to cardiovascular regulation.