Lipid signaling in cardiovascular afferent transmission

项目摘要 一过性受体电位香草样1型受体(TRPV1)存在于颅脑中央终末 孤束核(NTS)内包括动脉压力感受器和呼吸道传入的内脏传入 但中心TRPV1的功能尚不清楚。TRPV1是一种钙通道，有三个独立的“开口器”。 香草酸、酸碱度和温度。我们最近的细胞研究表明，TRPV1钙控制着 独立调节的谷氨酸囊泡池，有别于由动作释放的囊泡池 潜力。TRPV1操作的小泡产生自发的兴奋性突触事件(EPSCs)。行动 电压激活的钙通道与TRPV1操作的钙通道分别触发电位诱发的EPSCs 谷氨酸的释放。冷却到非生理温度30°C会抑制TRPV1的释放和 香草素类激动剂能敏化热敏感性。目前的建议源于观察到在动物中 给予高脂饮食(HFD)，阻断内侧NTS内的TRPV1受体可降低血压和心脏 费率。饲喂对照饲料的动物对TRPV1阻断无反应，提示存在内源性脂质激动剂 用HFD诱导的NTS。我们将研究ST TRPV1驱动谷氨酸的机制 在接触HFD期间和正常情况下传播。我们在体内的初步结果表明，HFD 产生一个类似香草素的调节剂，控制NTS内的传入触发反射功能。研究报告 计划建议建立香草素在ST传入传递中的作用机制，重点是 中枢神经系统在主动脉压力感受性反射控制中的作用我们的全球假说认为ST TRPV1作为一个焦点 NTS中多个信号的积分器，主要报告输出为谷氨酸释放。具体目标 将研究TRPV1操作的谷氨酸是否激活GABA上的代谢性谷氨酸受体 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受体是否改变HFD中有髓压力感受器的传递以及TRPV1是如何改变的 HFD期间NTS的激活改变了压力感受性反射反应。我的实验室对TRPV1有丰富的经验 外周压力感受器、压力感受器反射和中央ST段传导的机制。我们将依靠 方法包括电生理、活细胞成像、染料示踪和全动物反射测定 了解TRPV1从细胞到反射的功能特征。我们将与马登实验室合作 动物评估。提出的研究将有助于我们更好地理解这些神经的正常基础。 控制机制以及确定病理生理变化，并阐明动态平衡控制 包括中枢神经系统炎症、高血压、中风、代谢综合征、 心力衰竭会改变自主神经反射，从而产生有害影响。

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.