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

基本信息

批准号：
10299245
负责人：
Nikolaos Michael Tsoukias
金额：
$ 54.09万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10299245
关键词：
Action Potentials Affect Alzheimer&apos 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

项目摘要

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.

概括神经元活性导致局部脑血流（CBF）增加，以允许O2和活性神经元的营养。该过程称为神经血管耦合（NVC），对于生存及其其生存至关重要破坏与认知能力下降和痴呆有关。尽管有重大发现，我们仍然远离对NVC有全面的了解。这禁止我们对正常的彻底理解大脑功能以及确定疾病的关键失败并阻碍对血管起源的研究认知障碍。该应用的目的是研究K+介导的本地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AIM 1中，将开发内皮和平滑肌细胞的模型，并检查毛细血管和动脉中的K+介导的电信号传导。我们建议向内纠正K+ 当细胞外K+增加时，通道可作为Bistable，“ On-Ow-Own”，切换到超极化细胞膜。多- 微血管网络的细胞模型将检查毛细血管及其进食之间的通信小动脉，以及毛细血管级NVC对局部CBF控制的重要性。我们提出了再生信号传播可以实现此通信，我们将使用建模和前视频完整测试该假设动脉毛细血管制剂。在AIM 2中，几何准确的血管网络中的模拟将预测功能激活后血流的宏观变化。我们将将理论和实验整合到分析脑小血管和阿尔茨海默氏病的动物模型中的通道病状缺陷。我们将测试毛细血管 - 尿路通信受损并改变肌源反应的假设导致 NVC赤字和提议恢复这种赤字的最佳策略。拟议的工作将提供范式为了全面检查脑血流控制，用于解释改变的细胞信号传导疾病和阐明认知障碍中的血管基础。