Lipid signaling in cardiovascular afferent transmission

心血管传入传输中的脂质信号传导

• 批准号: 9158836
• 负责人: Michael Christian Andresen
• 金额: $ 44.79万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158836
• 关键词: Action Potentials; Affect; Afferent Pathways; Affinity; Agonist; Animal Feed; Animals; Attenuated; Baroreflex; Biological Assay; Blood Circulation; Blood Pressure; Blood Vessels; Brain; Brain Stem; Breathing; C Fiber; CNR1 gene; Calcium Channel; Calcium-Sensing Receptors; Cannabinoids; Capsaicin; Cardiovascular system; Cells; Cephalic; Characteristics; Communication; Complex; Diet; Disease; Dyes; Electrophysiology (science); Event; Exposure to; Fatty acid glycerol esters; Functional disorder; GABA Receptor; Glutamates; Goals; Heart; Heart Rate; Heart failure; Heating; High Fat Diet; Hypertension; Hypotension; Hypoxia; In Vitro; Inflammation; Institutes; Investigation; Laboratories; Life; Ligands; Light; Lipid Binding; Lipids; Lung; Medial; Mediating; Mediator of activation protein; Metabolic syndrome; Metabotropic Glutamate Receptors; Methods; Mission; Molecular; Morbidity - disease rate; Neuraxis; Neurons; Nucleus solitarius; Obesity; Output; Peripheral; Pressoreceptors; Process; Rattus; Receptor Activation; Reflex action; Reflex control; Regulation; Reporting; Research; Research Design; Resolution; Role; Sensory; Signal Transduction; Site; Stroke; Synapses; Synaptic Transmission; Testing; Unconscious State; Vanilloid; Vesicle; Visceral; Visceral Afferents; autonomic reflex; base; blood pressure reduction; cold temperature; design; endovanilloid; experience; gamma-Aminobutyric Acid; in vivo; interest; lipid metabolism; live cell imaging; mortality; neuromechanism; neuroregulation; novel; postsynaptic; presynaptic; receptor; receptor function; research study; response; stem; transmission process; vesicular release; voltage

Project Summary Transient Receptor Potential Vanilloid Type 1 Receptors (TRPV1) are present in the central terminals of cranial visceral afferents including arterial baroreceptors and airway afferents within the solitary tract nucleus (NTS) but the function of central TRPV1 is unclear. TRPV1 is a calcium channel with three separate “openers” vanilloids, pH, and heat. Our recent cellular investigations demonstrate that TRPV1 calcium controls an independently regulated pool of glutamate vesicles that is distinct from the pool of vesicles released by action potentials. TRPV1-operated vesicles generate spontaneous excitatory synaptic events (EPSCs). Action potential evoked EPSCs are triggered by voltage activated calcium channels separately from TRPV1-operated glutamate release. Cooling to unphysiologically low temperatures 30°C suppresses TRPV1 release and vanilloid agonists sensitize thermal sensitivity. The present proposal stems from the observation that in animals fed a high fat diet (HFD), blockade of TRPV1 receptors within medial NTS reduces blood pressure and heart rate. Animals fed control diets do not respond to TRPV1 blockade suggesting an endogenous lipid agonist induced in NTS by the HFD. We will examine the mechanisms by which ST TRPV1 drives glutamate transmission normally and during exposure to a HFD. Our in vivo preliminary results suggest that HFD generates a vanilloid-like mediator which controls afferent triggered reflex function within NTS. The Research Plan proposes to establish the mechanisms of action of vanilloids in ST afferent transmission with a focus on CNS function in aortic baroreflex control. Our global hypothesis proposes that ST TRPV1 serves as a focal integrator of multiple signals in NTS with a primary reporting output of glutamate release. The Specific Aims will investigate whether TRPV1-operated glutamate activates metabotropic glutamate receptors on GABA release, whether postsynaptic depolarization modulates presynaptic TRPV1 mediated glutamate release, whether B-type GABA receptors alter myelinated baroreceptor transmission during HFD and how TRPV1 activation in NTS during HFD alters baroreflex responses. My laboratory has extensive experience with TRPV1 mechanisms in peripheral baroreceptors, baroreceptor reflexes, and central ST transmission. We will rely on methods including electrophysiological, live cell imaging, dye tracing and assays of whole animal reflex characteristics to understand TRPV1 function from cell to reflex. We will team with the Madden lab for whole animal assessments. The proposed research will help us to better understand the normal basis of these neural control mechanisms as well as identify pathophysiological changes and shed light on homeostatic control that include consequences for central nervous system inflammation, hypertension, stroke, metabolic syndrome, and heart failure to alter autonomic reflexes to detrimental effect.

项目概要 瞬时受体电位香草酸 1 型受体 (TRPV1) 存在于颅骨中央末端 内脏传入神经包括孤束核 (NTS) 内的动脉压力感受器和气道传入神经 但中枢TRPV1的功能尚不清楚。 TRPV1 是一个钙通道，具有三个独立的“开启者” 香草醛、pH 值和热量。我们最近的细胞研究表明 TRPV1 钙控制 独立调节的谷氨酸囊泡池，与作用释放的囊泡池不同 潜力。 TRPV1 操作的囊泡产生自发的兴奋性突触事件 (EPSC)。行动 电位诱发 EPSC 由电压激活的钙通道触发，与 TRPV1 操作分开 谷氨酸释放。冷却至非生理低温 30°C 会抑制 TRPV1 释放， 香草酸激动剂可提高热敏感性。目前的提议源于对动物的观察 喂养高脂肪饮食 (HFD)，阻断内侧 NTS 内的 TRPV1 受体可降低血压和心脏功能 速度。饲喂对照饮食的动物对 TRPV1 阻断没有反应，表明存在内源性脂质激动剂 由 HFD 诱导的 NTS。我们将研究 ST TRPV1 驱动谷氨酸的机制 正常传输以及暴露于 HFD 期间。我们的体内初步结果表明 HFD 产生类香草酸介导物，控制 NTS 内的传入触发反射功能。研究 计划建议建立香草酸在 ST 传入传输中的作用机制，重点是 中枢神经系统在主动脉压力反射控制中的功能。我们的全局假设提出 ST TRPV1 作为焦点 NTS 中多个信号的积分器，主要报告谷氨酸释放的输出。具体目标 将研究 TRPV1 操作的谷氨酸是否激活 GABA 上的代谢型谷氨酸受体 释放，突触后去极化是否调节突触前 TRPV1 介导的谷氨酸释放， B 型 GABA 受体是否会改变 HFD 期间有髓鞘压力感受器的传递以及 TRPV1 如何改变 HFD 期间 NTS 的激活改变了压力反射反应。我的实验室在 TRPV1 方面拥有丰富的经验 外周压力感受器、压力感受器反射和中枢 ST 传输的机制。我们将依靠 方法包括电生理学、活细胞成像、染料示踪和整个动物反射测定 特征来了解 TRPV1 从细胞到反射的功能。我们将与 Madden 实验室合作 动物评估。拟议的研究将帮助我们更好地理解这些神经的正常基础 控制机制以及识别病理生理变化并阐明稳态控制 包括中枢神经系统炎症、高血压、中风、代谢综合征的后果， 和心力衰竭改变自主神经反射产生有害影响。