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.

概括 神经元活动导致局部脑血流量 (CBF) 增加，以提供充足的 O2 和 这个过程被称为神经血管耦合（NVC），对于生存及其生存至关重要。 干扰与认知能力下降和痴呆有关，尽管有重大发现，但我们距离这一目标还很远。 对NVC的全面了解阻碍了我们对正常情况的透彻了解。 大脑功能和识别疾病的严重故障并阻碍对血管起源的研究 本应用的目的是研究 K+ 介导的局部 CBF 控制。 这是通过神经输入和自动调节反馈的整合来实现的。 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模型并 检查毛细血管和小动脉中 K+ 介导的电信号传导，我们建议内向整流 K+。 当细胞外 K+ 增加时，通道充当双稳态“开关”，切换到超极化细胞膜。 微血管网络的细胞模型将检查毛细血管及其摄食之间的通讯 我们提出再生信号。 传播使这种交流成为可能，我们将使用建模和体外完整测试这个假设 在目标 2 中，几何精确的血管网络中的模拟将进行预测。 功能激活后血流的宏观变化我们将结合理论和实验来进行。 我们将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。 检验以下假设：毛细血管-小动脉通讯受损和肌源性反应会导致 NVC 赤字并提出恢复这种赤字的最佳策略。拟议的工作将提供一个范例。 用于脑血流控制的综合检查，用于解释细胞信号传导 疾病并阐明认知障碍的血管基础。