Glial regulation of neurovascular coupling in CNS disorders

神经胶质细胞对中枢神经系统疾病中神经血管耦合的调节

基本信息

批准号：
10584611
负责人：
Anusha Mishra
金额：
$ 33.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584611
关键词：
Acute Adult Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Arachidonic Acids Arteries Astrocytes Attenuated Automobile Driving Blood Glucose Blood Vessels Blood capillaries Blood flow Brain Central Nervous System Central Nervous System Diseases Cerebrovascular Circulation Cerebrovascular Disorders Clinic Data Deterioration Development Dinoprostone Disease Disinhibition EP4 receptor Environment Enzymes Equilibrium Evolution Exhibits Experimental Models Functional disorder Gene Expression Profile Goals Hydroxyeicosatetraenoic Acids Infarction Injury Maps Mediating Metabolic Middle Cerebral Artery Occlusion Mixed Function Oxygenases Modeling Molecular Monitor Morphology Multiple Sclerosis Nervous System Physiology Neurologic Neurons Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Nutrient Oxygen Pathway interactions Pattern Perfusion Pericytes Process Production Prognosis Prostaglandin-Endoperoxide Synthase Protein Isoforms Rattus Regulation Role Signal Pathway Signal Transduction Slice Stroke Testing Therapeutic Therapeutic Intervention Therapeutic Uses Time Tissues Translating Traumatic Brain Injury Up-Regulation Vasoconstrictor Agents Vasodilator Agents Viral acute stroke arteriole astrogliosis attenuation clinically relevant constriction experimental study in vivo metabotropic glutamate receptor 5 nervous system disorder neurological recovery neuropathology neurovascular neurovascular coupling post stroke prevent receptor response restoration spatiotemporal stroke model stroke patient therapeutic target therapeutically effective vasoconstriction

项目摘要

PROJECT SUMMARY Increased neuronal activity in the central nervous system (CNS) elicits corresponding increases in local cerebral blood flow. This response, termed neurovascular coupling, is lost or attenuated in several CNS disorders, including stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and traumatic brain injury (TBI). The resulting decrease in blood glucose and oxygen available to actively firing and recovering neurons is likely to exacerbate neuronal damage and contribute to neurological deterioration. Therefore, a key goal of therapeutic management in these conditions includes restoration of blood flow. However, the mechanisms underlying the attenuation of neurovascular coupling in disease are unknown, complicating the development of effective therapeutics for use in the clinic. We have previously demonstrated that astrocytes are necessary intermediates that convey signals from metabolically active neurons to microvascular capillaries but not arterioles. Of relevance to this proposal, astrocytes are also exquisitely sensitive to changes in their environment and become reactive in response to CNS insults. This response encompasses drastic changes in astrocyte morphology and gene expression patterns, but the consequence of these changes on neurovascular coupling remain undefined. We hypothesize that aberrant signals from reactive astrocytes are responsible for the attenuation of neurovascular coupling in injury or disease. Our preliminary data support this hypothesis: after an experimental model of stroke wherein astrocyte reactivity is induced, activity-dependent dilation is significantly attenuated at capillaries, the vascular compartment regulated by astrocytes. Therefore, our goal is to determine the mechanism(s) by which reactive astrocytes might suppress capillary dilation. Specifically, we will test the hypothesis that neurovascular coupling is suppressed selectively at capillaries but not arterioles following stroke (Aim 1), determine whether activity-evoked responses of reactive astrocytes are selectively altered in astrocyte endfeet terminating on capillaries but not on arterioles (Aim 2), and identify the signaling pathways responsible for the suppression of activity-evoked capillary dilation (Aim 3).

项目摘要中枢神经系统（CNS）中的神经元活性增加了局部的相应增加脑血流。这种称为神经血管耦合的反应在几个CNS中丢失或减弱疾病，包括中风，阿尔茨海默氏病（AD），肌萎缩性侧面硬化症（ALS），多发性硬化症（MS）和创伤性脑损伤（TBI）。可积极可用的血糖和氧气减少开火和恢复神经元可能会加剧神经元损害，并导致神经系统恶化。因此，在这些条件下治疗管理的关键目标包括恢复血流（量。但是，疾病中神经血管耦合衰减的基础机制是未知，使有效的治疗剂用于诊所使用。我们以前有证明星形胶质细胞是从代谢活动中传达信号的必要中间体神经元至微血管毛细血管，而不是小动脉。与该建议相关的是，星形胶质细胞也是对环境的变化非常敏感，并对中枢神经系统的侮辱变得反应性。这反应包括星形胶质细胞形态和基因表达模式的急剧变化，但这些变化对神经血管耦合的结果仍然不确定。我们假设这种异常反应性星形胶质细胞的信号负责受伤或疾病。我们的初步数据支持这一假设：在实验模型的中风模型之后诱导反应性，依赖活性依赖性扩张在毛细血管处显着减弱，血管由星形胶质细胞调节的腔室。因此，我们的目标是确定反应性的机制星形胶质细胞可能抑制毛细血管扩张。具体而言，我们将测试神经血管的假设毛细管在毛细血管上有选择地抑制耦合，但在中风后没有小动脉（AIM 1），确定是否确定是否是否反应性星形胶质细胞的活性诱发反应有选择地改变了星形胶质细胞终止的终止。毛细血管，但不在小动脉上（AIM 2），并确定负责抑制的信号传导途径活动引起的毛细血管扩张（AIM 3）。