Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease

毛细血管作为控制健康和疾病中脑血流的感觉网

基本信息

批准号：
10306351
负责人：
MARK T NELSON
金额：
$ 90.6万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
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：
2019-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10306351
关键词：
Arteries Astrocytes Blood Vessels Blood capillaries Blood flow Brain Brain Diseases Calcium Capillary Endothelial Cell Cerebrovascular Circulation Cerebrovascular system Communication Complex Computer Models Coupled Data Dinoprostone Disease Endothelium Equilibrium G alpha q Protein Goals Health Internet Kinetics Mediating Mediator of activation protein Membrane Metabolic Microvascular Dysfunction Molecular Neurons Nitric Oxide Nutrient Oxygen Perfusion Pericytes Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Physiological Potassium Receptor Signaling Regulation Research Role Sensory Signal Transduction Site System Testing Time Vascular blood supply arteriole base biophysical model cerebral capillary cerebral microvasculature cerebrovascular feeding in silico in vivo insight inward rectifier potassium channel molecular modeling neurovascular coupling novel operation parenchymal arterioles response

项目摘要

PROJECT SUMMARY Neurons in the brain have limited energy reserves and thus rely on a “just-in-time” delivery strategy in which active neurons signal to the brain microvasculature to increase regional cerebral blood flow (CBF), resupplying nutrients and oxygen as well as removing toxic metabolites. Despite extensive study, the mechanisms underlying the functional linkage between neuronal metabolic demand and vascular supply, termed neurovascular coupling (NVC), remain poorly understood. Blood flow to the brain is mediated by parenchymal arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. We recently presented evidence supporting the concept that brain capillaries act as a neuronal activity-sensing network, demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical (hyperpolarizing) signal in response to neuronal activity that propagates upstream to cause dilation of feeding arterioles and increase blood flow locally at the site of signal initiation. We have established the mechanistic basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have recently discovered that a second fundamental NVC mechanism based on calcium (Ca2+) signaling, with distinct kinetics and regulatory features, also operates in brain capillaries, and can be initiated by the putative NVC mediator prostaglandin E2 (PGE2). We have further found that a mechanism initiated by Gq-protein coupled receptor signaling and mediated by dynamic changes in membrane phosphatidylinositol 4,5- bisphosphate (PIP2) levels controls the balance between electrical and Ca signaling. Additional preliminary 2+ data support a role for gasotransmission via Ca2+-dependent endothelial nitric oxide signaling and pericyte- mediated regulation of capillary blood flow in modulating NVC. The immediate goals of this proposal are to create an integrated view of electrical, Ca2+ and related regulatory signaling mechanisms at molecular, biophysical, and computational-modeling levels by examining their operation in increasingly complex segments of the brain vasculature ex vivo, in vivo, and in silico. Ultimately, we propose to weave these research threads together to create a systems-level view of physiological capillary-to-arteriole/pial artery signaling in the brain, and test the concept that gradual degradation of this sensory web and the attendant progressive decay of cerebrovascular function contributes to small vessel diseases of the brain.

项目概要大脑中的神经元的能量储备有限，因此依赖于“及时”的传递策略，其中活跃的神经元向大脑微血管发出信号，增加局部脑血流量 (CBF)，重新供应尽管进行了大量研究，但其机制仍不清楚。神经代谢需求和血管供应之间的功能联系的基础，称为神经血管耦合（NVC）仍然知之甚少，流向大脑的血流是由实质细胞介导的。小动脉和数百英里的毛细血管，极大地扩展了灌注范围。提出了支持脑毛细血管作为神经活动感知网络这一概念的证据，证明脑毛细血管内皮细胞（cEC）能够启动电（超极化）信号响应神经元活动，向上游传播导致进食扩张我们已经建立了机制。该电信号的基础，表明神经元和/或星形胶质细胞来源的钾 (K+) 是关键介体并确定强内向整流 K+ 通道 Kir2.1 作为关键分子。最近发现了基于钙 (Ca2+) 信号传导的第二种基本 NVC 机制，独特的动力学和调节特征，也在脑毛细血管中起作用，并且可以由假定的启动我们进一步发现了NVC介导的前列腺素E2（PGE2）是由Gq蛋白启动的机制。耦合受体信号传导并由膜磷脂酰肌醇 4,5- 的动态变化介导二磷酸盐 (PIP2) 水平控制电信号和 Ca 信号传导之间的平衡。 2+ 数据支持通过 Ca2+ 依赖性内皮一氧化氮信号传导和周细胞进行气体传输的作用调节 NVC 中毛细血管血流的介导调节该提案的直接目标是在分子、Ca2+ 和相关调节信号机制方面创建一个综合视图通过检查它们在日益复杂的部分中的操作来提高生物物理和计算建模水平最终，我们建议编织这些研究线索。共同创建大脑中生理毛细血管到小动脉/软脑膜动脉信号传导的系统级视图，并测试这种感觉网逐渐退化以及随之而来的逐渐衰退的概念脑血管功能导致大脑小血管疾病。