The role of the endothelial NPYR1-TRPC3-ET1 signaling axis in neurovascular coupling dysfunction

内皮NPYR1-TRPC3-ET1信号轴在神经血管耦合功能障碍中的作用

基本信息

批准号：
10667097
负责人：
FANG ZHENG
金额：
$ 38.6万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667097
关键词：
Acute Address Adrenergic Agents Aging Agonist Anticonvulsants Area Astrocytes Binding Blood Glucose Blood Vessels Blood flow Brain Brain Injuries Cations Cells Cephalic Cerebrovascular Circulation Cerebrum Clinical Consumption Core-Binding Factor Coupling Data Electroencephalography Endothelial Cells Endothelin A Receptor Endothelin Receptor Endothelin-1 Endothelium Epilepsy Event Functional disorder Harvest Interneurons Knock-out Knockout Mice Laser Speckle Imaging Mediating Modeling Molecular Target Monitor Mus Muscle Cells Nerve Degeneration Neurological outcome Neurons Neuropeptide Y Receptor Oxygen Pathogenicity Pathologic Pharmaceutical Preparations Pilocarpine Play Predisposition Preparation Process Regional Blood Flow Research Role Seizures Signal Pathway Signal Transduction Smooth Muscle Myocytes Status Epilepticus TRP channel Testing Tissues Traumatic Brain Injury Vascular Smooth Muscle Vasoconstrictor Agents Vasodilation Vasodilator Agents antagonist arteriole awake cell type cerebral artery cerebrovascular constriction experimental study functional disability gamma-Aminobutyric Acid genetic approach hemodynamics improved in vivo inhibitor insight nervous system disorder neuroinflammation neuronal metabolism neuropeptide Y neurovascular coupling neurovascular unit novel parenchymal arterioles pharmacologic receptor response vasoconstriction

项目摘要

This R01 application focuses on the underlying mechanisms of neurovascular coupling dysfunction. The brain consumes a large amount of energy which must be supplied as oxygen and glucose by blood flow. Neurovascular coupling, a mechanism that matches local neuronal activity to blood flow, is critical to maintain local microenvironment and normal brain function. However, normal neurovascular coupling is disrupted in seizure, traumatic brain injury, and other neurological disorders. Despite continued high neuronal metabolism, small cerebral arteries and arterioles begin to inappropriately constrict to limit CBF to the challenged neurons. This pathogenic vasoconstriction, termed the “inverse hemodynamic response” (IHR), is thought to contribute to brain damage and functional impairment in these neurological diseases. The mechanism of IHR is unknown. This proposal seeks to test a novel hypothesis that seizure-induced IHR is mediated by an endothelial signaling pathway consisted of Neuropeptide Y Receptor 1 (NPYR1), Transient Receptor Potential (Canonical) 3 (TRPC3) channels, and endothelin 1 (ET1). We generated inducible and brain-specific endothelial TRPC3 knockout line and NPYR1 knockout line. These novel mouse lines will be used in combination with NPYR1, TRPC3 and ET1 receptor selective inhibitors to test our hypothesis. Aim 1 will demonstrate the existence of an endothelial NPYR1-TRPC3-ET1 signaling pathway that mediates cerebral vasoconstriction using acutely isolated brain parenchymal arterioles and cranial window preparations in vivo. Aim 2 will show that the same signaling pathway mediates seizure-induced IHR. Aim 3 will determine whether disruption of this signaling pathway will reduce susceptibility to seizures and their deleterious consequences. The studies rely on complementary areas of expertise pooled by a research team with expertise in cerebrovascular reactivity, epilepsy and neuroinflammation and neurodegeneration. Collectively, these experiments will reveal new mechanistic insights regarding IHR and may lead to new treatments for epilepsy and other neurological diseases.

该 R01 应用重点关注神经血管耦合功能障碍的潜在机制。消耗大量能量，必须通过血流以氧气和葡萄糖的形式提供。耦合是一种将局部神经活动与血流相匹配的机制，对于维持局部神经活动至关重要微环境和正常脑功能然而，正常的神经血管耦合在癫痫发作时被破坏。外伤性脑损伤和其他神经系统疾病尽管神经元代谢持续高，但小。脑动脉和小动脉开始不适当地收缩，以限制 CBF 到达受攻击的神经元。致病性血管收缩，称为“逆血流动力学反应”（IHR），被认为有助于这些神经系统疾病的脑损伤和功能障碍的机制尚不清楚。该提案旨在检验一个新的假设，即癫痫发作诱发的 IHR 是由内皮信号传导介导的神经肽 Y 受体 1 (NPYR1)、瞬时受体电位（规范）3 (TRPC3) 遵循的途径我们生成了诱导型和脑特异性内皮 TRPC3 敲除系。这些新型小鼠品系将与 NPYR1、TRPC3 和 ET1 组合使用。受体选择性抑制剂来检验我们的假设，目标 1 将证明内皮细胞的存在。利用急性离体脑介导脑血管收缩的 NPYR1-TRPC3-ET1 信号通路体内实质小动脉和颅窗制备物将显示相同的信号传导。途径介导癫痫发作诱导的 IHR 目标 3 将确定该信号途径的破坏是否会产生影响。降低癫痫发作及其有害后果的易感性这些研究依赖于互补领域。由具有脑血管反应性、癫痫和总的来说，这些实验将揭示新的机制。关于《国际卫生条例》的见解可能会带来癫痫和其他神经系统疾病的新疗法。