Cerebral Microvascular Signaling and Neurovascular Coupling: An Integrated Approach to Investigate VCID

脑微血管信号传导和神经血管耦合：研究 VCID 的综合方法

• 批准号: 10459515
• 负责人: Nikolaos Michael Tsoukias
• 金额: $ 52.39万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459515
• 关键词: Action Potentials; Affect; Alzheimer' s Disease; Animal Model; Astrocytes; Biophysics; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Pathology; Caliber; Capillary Endothelial Cell; Cell membrane; Cells; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; Chemicals; Cognition Disorders; Communication; Complex; Data; Defect; Dementia; Disease; Endothelium; Environment; Failure; Feedback; Health; Homeostasis; Hyperemia; Impaired cognition; Impairment; Investigation; Ions; Lead; Link; Location; Mathematics; Mediating; Mediator of activation protein; Microcirculation; Microscopic; Microvascular Dysfunction; Modeling; Neurons; Nutrient; Oxygen; Perfusion; Pharmacology; Preparation; Process; Public Health; Recovery; Research; Resources; Role; Scanning; Seminal; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stroke; Techniques; Testing; Tissues; Vascular Endothelium; Vascular Smooth Muscle; Waste Products; Work; arteriole; base; blood perfusion; cell type; economic implication; experimental study; extracellular; feeding; foot; insight; inward rectifier potassium channel; mathematical model; member; multi-scale modeling; neuroimaging; neurotransmission; neurovascular coupling; novel strategies; parenchymal arterioles; pressure; regenerative; response; sensor; simulation; social implication; targeted treatment; theories; vascular cognitive impairment and dementia

SUMMARY Neuronal activity leads to increases in local cerebral blood flow (CBF) to allow adequate supply of O2 and nutrients to active neurons. This process, termed neurovascular coupling (NVC), is essential for survival and its disruption is associated with cognitive decline and dementia. Despite significant findings, we are still far from reaching a comprehensive understanding of NVC. This prohibits us from a thorough understanding of normal brain function and from identifying critical failures in disease and hinders investigations into the vascular origins of cognitive impairment. The objective of this application is to investigate how K+-mediated local CBF control emerges from the integration of neuronal inputs and autoregulatory feedback. This will be accomplished by pursuing two specific aims: In Aim 1, models of endothelial and smooth muscle cells will be developed and examine K+-mediated electrical signaling in capillaries and arterioles. We propose that the inward rectifying K+ channel acts as bistable, “on-off”, switch to hyperpolarize cell membranes when extracellular K+ increases. Multi- cellular models of microvascular networks will examine communication between capillaries and their feeding arteriole, and the significance of capillary-level NVC for local CBF control. We propose that regenerative signal propagation enables this communication and we will test this hypothesis using modeling and an ex-vivo intact arteriole-capillary preparation. In Aim 2, simulations in a geometrically accurate vascular network will predict macroscopic changes in blood flow following functional activation. We will integrate theory and experiments to analyze channelopathy-like defects, in animal models of cerebral small vessel and Alzheimer's disease. We will test the hypothesis that impaired capillary-arteriole communication and altered myogenic response lead to a NVC deficit and propose optimal strategies for restoring this deficit. The proposed work will provide a paradigm for comprehensive examinations of cerebral blood flow control, for interpreting altered cellular signaling in disease and for elucidating vascular underpinnings in cognitive impairment.

摘要 神经元活动导致局部脑血流量(CBF)增加，以允许足够的O2和 营养物质给活跃的神经元。这个过程被称为神经血管偶联(NVC)，对于生存和它的 精神分裂与认知能力下降和痴呆症有关。尽管有重大发现，但我们仍远未 对NVC有了全面的了解。这妨碍了我们对正常的透彻理解 大脑功能和识别疾病中的关键故障，并阻碍对血管起源的调查 认知障碍的症状。该应用程序的目的是研究K+介导的局部CBF控制 从神经元输入和自动调节反馈的整合中出现。这将通过以下方式实现 追求两个具体目标：在目标1中，将建立内皮细胞和平滑肌细胞模型，并 检查K+介导的毛细血管和小动脉的电信号。我们提出内向整流K+ 当细胞外K+增加时，通道起到双稳态、“开-关”的作用，使细胞膜发生超极化。多个- 微血管网络的细胞模型将检查毛细血管和它们的供血之间的联系。 毛细血管水平NVC对局部CBF控制的意义。我们提出再生信号 传播使这种交流成为可能，我们将使用建模和完整的体外实验来验证这一假设 微动脉-毛细血管制剂。在目标2中，在几何上精确的血管网络中的模拟将预测 功能激活后血液流动的宏观变化。我们将把理论和实验相结合，以 分析脑部小血管和阿尔茨海默病动物模型中的经络病样缺陷。我们会 验证毛细血管-小动脉通讯受损和肌源性反应改变会导致 并提出修复这一赤字的最佳策略。拟议的工作将提供一个范例 用于脑血流控制的全面检查，用于解释脑内细胞信号的变化 并用于阐明认知障碍的血管基础。