权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Vascular Signaling Plasticity - Novel Concepts and Tools for Studying Neurovascular Interactions in Health and Disease

血管信号可塑性 - 研究健康和疾病中神经血管相互作用的新概念和工具

基本信息

批准号：
10002378
负责人：
Thomas A Longden
金额：
$ 231.75万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-03-31
项目状态：
未结题

项目摘要

SUMMARY The brain requires a vast amount of energy (around 20% of the total generated in the body) to function normally. Despite this, the brain lacks energy stores and instead uses a ‘just-in-time’ energy delivery system known as ‘functional hyperemia’, in which local blood flow increases in response to spikes in neuronal activity. This process is underlain by a range of redundant ‘neurovascular coupling’ mechanisms that collectively ensure the fidelity of the blood flow response to feed activity. We have discovered that these mechanisms display a striking form of plasticity, in which chronic changes in neuronal energy requirements lead to reprogramming of these vascular signaling mechanisms to augment or dampen the local delivery of blood. We term this phenomenon vascular signaling plasticity (VSP). Importantly, VSP is disrupted in a mouse model of Alzheimer’s disease, implying that loss of this process may lead to a mismatch between energy supply and demand and impair neuronal function. Here, we propose a program of research in which we develop novel workflows for chronic imaging of VSP in awake behaving animals, followed by detailed molecular analyses of the mechanisms that underlie VSP in the same cells that we image. This work will reveal a previously unknown and unsuspected mechanism for blood flow control in the brain that is critical for neuronal health, opening a new field of research into the phenomenon of VSP. Completion of this project will deliver a range of imaging tools to enable us to image blood flow and aspects of VSP non-invasively over long periods in vivo, and our work will culminate in the development of a novel brain endothelium-specific gene therapy aimed at protecting or restoring VSP in dementia, thereby safeguarding neuronal metabolism and function.

概括大脑需要大量能量（约占体内产生的总能量的 20%）才能正常运作。尽管如此，大脑缺乏能量储存，而是使用一种“及时”能量输送系统，称为 “功能性充血”，局部血流量因神经元活动的峰值而增加。这个过程其背后是一系列冗余的“神经血管耦合”机制，这些机制共同确保了血流对饲料活动的反应。我们发现这些机制表现出一种引人注目的形式可塑性，其中神经元能量需求的慢性变化导致这些血管的重新编程增强或抑制局部血液输送的信号机制。我们将这种现象称为血管性信号可塑性（VSP）。重要的是，VSP 在阿尔茨海默病小鼠模型中被破坏，这意味着这一过程的丧失可能会导致能量供需之间的不匹配并损害神经元功能。在这里，我们提出了一个研究计划，其中我们开发了用于 VSP 慢性成像的新颖工作流程清醒行为的动物，然后对 VSP 的机制进行详细的分子分析与我们成像的细胞相同。这项工作将揭示一种以前未知和未曾怀疑的血液机制大脑中的流量控制对神经元健康至关重要，为这一现象的研究开辟了新领域 VSP 的。该项目的完成将提供一系列成像工具，使我们能够对血流和体内长时间非侵入性地研究 VSP 的各个方面，我们的工作将最终开发出一种新型脑内皮特异性基因疗法旨在保护或恢复痴呆症的 VSP，从而保护神经元的代谢和功能。