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）：瞬时受体电位 1 型香草酸受体 (TRPV1) 有助于检测脊髓初级传入伤害感受器产生的有害热量 (>420C) 和组织损伤。该提案将研究孤束核 (NTS) 内颅初级传入神经中 TRPV1 表达控制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 机制在生理温度下很活跃，并以传入活动依赖性方式增强谷氨酸的持久释放 - 后者是突触可塑性的一种新形式。这种新形式的谷氨酸传输仅存在于辣椒素敏感的孤束传入神经的传输中。该研究计划建议建立 TRPV1 在 ST 传入传输中的作用机制，重点关注中枢神经系统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末梢的 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 充当增益变阻器 - 增加或减少无髓鞘压力感受器传入的影响。我们将研究NTS中TRPV1在组合与温度相关的信号中的作用； G 蛋白偶联受体、膜衍生的脂质介质和其他信号。初步研究表明，兴奋性谷氨酸小泡的异步TRPV1池的调节独立于同步谷氨酸小泡池，同步谷氨酸小泡池负责由传入动作电位在低抖动延迟下触发的兴奋性突触后电流——这是一个在所有孤束传入中看起来相同的同步释放过程。我的实验室在外周压力感受器、压力感受器反射和中枢 ST 传输方面的 TRPV1 机制方面拥有丰富的经验。研究将依赖于大鼠、小鼠和转基因小鼠的电生理学、活细胞成像、染料示踪和反射测定等方法。我们的具体目标包括评估传入活动依赖性异步谷氨酸释放生成中的大麻素信号传导、蛋白激酶 C 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。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，以便确定临床综合征的病理生理变化和新的治疗途径，这些临床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——所有这些都显示出自主神经反射改变的有害影响。 公共健康相关性：大脑包含神经元网络，这些神经元网络对于在与生命相适应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体循环以及适当的呼吸频率。该提议涉及大脑的一个关键部分，该部分是正常反射所必需的，可以对心脏、血管和肺部进行无意识的调整，从而为整个身体提供正常的条件。这些神经元有时在研究所使命内的疾病状态下功能异常，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功能的细胞机制以及它们与心血管调节的关系。