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: 10663254
• 负责人: Nikolaos Michael Tsoukias
• 金额: $ 51.85万
• 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/10663254
• 关键词: Action Potentials; Affect; Alzheimer' s Disease; Animal Model; Astrocytes; Biophysics; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Pathology; Capillary Endothelial Cell; Cell Communication; Cell membrane; Cell model; Cells; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; Chemicals; Cognition Disorders; Communication; Complex; Data; Defect; Dementia; Diameter; Disease; Endothelium; Environment; Failure; Feedback; Health; Homeostasis; Hyperemia; Impaired cognition; Impairment; Investigation; Ions; Lead; Link; Location; Mathematics; Mediating; Mediator; Microcirculation; Microscopic; Microvascular Dysfunction; Modeling; Neurons; Nutrient; Oxygen; Perfusion; Preparation; Process; Public Health; Recovery; Relaxation; 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; blood perfusion; cell type; economic implication; experimental study; extracellular; feeding; insight; inward rectifier potassium channel; mathematical model; member; multi-scale modeling; neuroimaging; neurotransmission; neurovascular coupling; novel strategies; parenchymal arterioles; pharmacologic; 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.

总结 神经元活动导致局部脑血流量（CBF）增加，以提供充足的O2供应， 为活跃的神经元提供营养。这一过程被称为神经血管偶联（NVC），是生存所必需的， 破坏与认知能力下降和痴呆症有关。尽管有重大发现，我们仍然远远没有 全面了解NVC。这使我们无法彻底理解正常的 大脑功能和识别疾病的关键故障，并阻碍调查血管起源 认知障碍本申请的目的是研究K+介导的局部CBF控制 来自神经元输入和自动调节反馈的整合。这将通过 追求两个具体目标：在目标1中，将开发内皮细胞和平滑肌细胞的模型， 检查毛细血管和小动脉中K+介导的电信号。我们认为内向整流K+ 当细胞外K+增加时，通道起着“开-关”的作用，转换到高钾细胞膜。多重 微血管网络的细胞模型将研究毛细血管和它们的喂养之间的通信 毛细血管水平NVC对局部CBF控制的意义。我们建议再生信号 传播使这种沟通，我们将测试这一假设使用建模和离体完整的 小动脉-毛细血管制备。在目标2中，在几何精确的血管网络中进行模拟将预测 功能激活后血流的宏观变化。我们将把理论和实验结合起来， 在脑小血管和阿尔茨海默病的动物模型中分析通道病样缺陷。我们将 检验毛细血管-小动脉通讯受损和肌源性反应改变导致 NVC赤字，并提出最佳策略，以恢复这一赤字。拟议的工作将提供一个范例 用于脑血流控制的全面检查，用于解释脑内改变的细胞信号传导， 疾病和阐明认知障碍的血管基础。