Central TRPV1 in Cardiovascular Regulation

TRPV1 在心血管调节中的中枢

• 批准号: 8213417
• 负责人: Michael Christian Andresen
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213417
• 关键词: Action Potentials; Afferent Neurons; Baroreflex; Biological Assay; Blood Circulation; Blood Pressure; Blood Vessels; Brain; Brain Part; Brain Stem; Breathing; C Fiber; Cannabinoids; Capsaicin; Cardiovascular system; Cephalic; Characteristics; Clinical; Communication; Data; Detection; Disease; Dyes; Evaluation; G-Protein-Coupled Receptors; Generations; Glutamates; Goals; Heart; Heart failure; Heating; Hypertension; Hypoxia; Inflammation; Institutes; Investigation; Laboratories; Life; Lung; Mediating; Membrane; Metabolic syndrome; Methods; Mission; Mus; Neuraxis; Neurons; Nociception; Nociceptors; Nucleus solitarius; Pain; Peripheral; Physiological; Pressoreceptors; Process; Protein Kinase C; Publishing; Qualifying; Rattus; Reflex action; Regulation; Research; Role; Signal Transduction; Site; Spinal; Stroke; Synaptic Transmission; Synaptic plasticity; Syndrome; System; Temperature; Testing; Thinking; Tissues; Transgenic Mice; Unconscious State; Vanilloid; Vesicle; Work; autonomic reflex; base; cellular imaging; design; experience; lipid mediator; mouse model; neuroregulation; novel; novel therapeutics; postsynaptic; pressure; presynaptic; public health relevance; receptor; receptor expression; response; stem; transmission process

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.

描述（由申请人提供）：瞬态受体电位1型受体（TRPV1）有助于检测有害热（> 420c）和脊柱原发性传入伤害感受器的组织损伤。该提案将检查孤立界核（NTS）内的TRPV1在颅主要传入中的TRPV1表达来控制一种新发现的突触传播形式 - TRPV1介导的异步谷氨酸透射传播。我们的初步研究表明，该TRPV1机制在生理温度下具有活性，并以传入的活动依赖性方式增强长期粘液剂的释放 - 后者是一种新的突触可塑性形式。这种新形式的谷氨酸传播仅存在于辣椒素敏感孤立的传入中。研究计划提出，建立TRPV1在ST传播传播中的作用机理，重点是心血管控制中的CNS功能。我们的全球假设提出，TRPV1位于突触前的颅骨传入终端是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是增益的变阻器 - 增加或减少了无髓鞘的压力受体传入的影响。我们将研究TRPV1在NTS在与温度相关的信号中的作用。 G蛋白偶联受体，膜得出的脂质介质和其他信号。初步工作表明，兴奋性谷氨酸囊泡的异步TRPV1池与负责兴奋性的突触后电流的同步谷氨酸囊泡池独立进行调节，该促兴奋性促进后电流在低抖动延迟的情况下通过传入动作潜力 - 同步释放过程 - 同步的释放过程，这些过程在所有人中似乎在孤立的牵引力中似乎是相同的。我的实验室在周围压力感受器，压力感受器反射和中央ST传输方面具有TRPV1机制的丰富经验。研究将依赖于大鼠，小鼠和转基因小鼠的组合中的电生理，活细胞成像，染料追踪和反射测定的方法。我们的具体目的包括评估大麻素信号在传入活性依赖性产生异步谷氨酸释放中，蛋白激酶C的需求，G蛋白耦合受体对敏化异步释放的贡献以及NTS TRPV1 TRPV1对心血管调节的影响。拟议的研究将帮助我们充分理解这些神经控制机制的正常基础，以鉴定临床综合征的病理生理变化和新的治疗途径，这些综合症可能包括中枢神经系统炎症，高血压，中风，代谢综合征和心脏失败的后果 - 所有这些表现出改变的自动反射性反射而变化。 公共卫生相关性：大脑包含神经元网络，这些网络对于在与生活兼容的状态中保持正常的身体功能至关重要。这些神经元网络形成反射，其中包括对足够血压支持系统循环以及适当呼吸速率的调节。该提案涉及大脑的关键部分，这是正常反射所需的，这些反射会在心脏，血管和肺部产生无意识的调整，这些调整可提供整个身体正常情况。这些神经元在研究所任务中的疾病状态中有时会异常起作用，例如高血压，缺氧，代谢综合征和心力衰竭，这项研究旨在了解控制这些神经元的细胞机制，以及它们与心血管调节的关系。