Central TRPV1 in Cardiovascular Regulation

点击翻译按钮获取中文摘要

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.