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

• 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
• 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

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应用集中在神经血管耦合功能障碍的基本机制上。大脑 消耗大量能量，必须作为氧气提供，并通过血流葡萄糖。神经血管 耦合是一种与局部神经元活性与血流相匹配的机制，对维持局部至关重要 微环境和正常的大脑功能。但是，正常的神经血管耦合是癫痫发作的， 创伤性脑损伤和其他神经系统疾病。尽管神经元代谢持续持续，但很小 脑动脉和动脉开始不当地收缩以将CBF限制为受到挑战的神经元。这 病原体血管收缩称为“逆血流动力学反应”（IHR），被认为有助于 这些神经系统疾病中的脑损伤和功能障碍。 IHR的机制是未知的。 该提案旨在检验一个新的假设，即癫痫发作诱导的IHR是由内皮信号传导介导的 途径由神经肽Y受体1（NPYR1）组成，瞬态受体电位（典型）3（TRPC3） 通道和内皮素1（ET1）。我们生成了诱导和大脑特异性的内皮TRPC3敲除线 和NPYR1淘汰线。这些新型小鼠系将与NPYR1，TRPC3和ET1结合使用 受体选择性抑制剂以检验我们的假设。 AIM 1将证明存在内皮的存在 NPYR1-TRPC3-ET1信号传导途径，使用急性分离的脑介导脑血管收缩 实质动物和颅窗制剂在体内。 AIM 2将表明相同的信号传导 途径介导癫痫发作引起的IHR。 AIM 3将确定该信号通路的破坏是否会 减少对癫痫发作及其有害后果的敏感性。研究依靠完整的领域 由具有脑血管反应性，癫痫和 神经炎症和神经变性。总的来说，这些实验将揭示新的机械 关于IHR的见解，可能会导致有关癫痫和其他神经系统疾病的新疗法。