Calcium signaling in the cerebrovascular unit in health and disease

该计划由四个项目和三个核心组成，重点研究脑实质（脑内）小动脉，它在脑内分配血液，并表现出独特的特性，尽管人们对其知之甚少。本研究的总体目标是阐明实质小动脉（PAs）内皮和平滑肌（SM）在缺血/再灌注（l/R）损伤和蛛网膜下腔出血（SAH）后正常调节血管张力和神经血管耦合（NVC）的分子机制。中心统一的主题是Ca2+信号的精确控制在组成“脑血管单位”的细胞-内皮，SM和星形胶质细胞-决定正常的脑功能；推而广之，Ca2+信号动力学功能障碍可导致脑血管疾病。每个项目研究生物系统的重叠元素以形成一个整体。项目1将首次提供关于PA内皮细胞（ECs）的特性和功能的信息，探索Ca2+信号和Ca2+敏感的SK和IK钾通道及其对SM功能和NVC的影响。项目2将专注于实质小动脉SM，重点是电压依赖性Ca2+通道（Cav）和瞬态受体电位（TRP）通道。项目1和2为项目3和4提供了平台。项目3将与项目1和项目2相互作用，探索I/R后发生的实质小动脉反应性深刻变化的潜在机制基础，重点关注离子通道功能的EC-SM变化。项目4关注的是SAH后的PAs和NVC，与项目2研究的是SAH对SM Cav和TRP通道的影响，与项目1研究的是内皮功能和NVC。由于内皮和SM在生理上是一个整体，项目1和项目2本质上是高度相互依存的。项目3和项目4侧重于两种不同但临床相关的病理条件下脑血管单元功能失调，依赖于项目1和项目2的信息。成像核心将为复杂系统中的Ca2+测量提供最先进的方法。动物和仪器核心将整合和协调所有动物和体内工作，包括开发新型遗传编码比例Ca2+生物传感器。长期目标是了解健康和疾病时大脑中的血液流动，并通过这样做，揭示可用于治疗脑血管疾病的令人兴奋的新靶点。

This Program, consisting of four Projects and three Cores, focuses on parenchymal (intracerebral) arterioles, which distribute blood within the brain and exhibit unique, albeit poorly understood, properties. The overall goal is to elucidate the molecular mechanisms by which the endothelium and smooth muscle (SM) of parenchymal arterioles (PAs) regulate vascular tone and neurovascular coupling (NVC) normally, and following ischemia/reperfusion (l/R) injury and subarachnoid hemorrhage (SAH). The central unifying theme is that the precise control of Ca2+ signaling in cells composing the "cerebrovascular unit"- endothelium, SM and astrocytes-determines normal brain function; by extension, dysfunction of Ca2+ signaling dynamics contributes to cerebrovascular disorders. Each project studies overlapping elements of the biological system to form a whole. Project 1 will provide the first information on properties and function of PA endothelial cells (ECs), exploring Ca2+ signaling and Ca2+-sensitive SK and IK potassium channels and their impact on SM function and NVC. Project 2 will focus on parenchymal arteriolar SM, with an emphasis on voltage-dependent Ca2+ channels (Cav) and transient receptor potential (TRP) channels. Projects 1 and 2 provide the platform for Projects 3 and 4. Project 3 will interact with Projects 1 and 2 to explore the underlying mechanistic basis for the profound changes in parenchymal arteriolar reactivity that develop following I/R, focusing on EC-SM changes in ion channel functionality. Project 4, which focuses on PAs and NVC following SAH, intersects with Project 2 on the effects of SAH on SM Cav and TRP channels, and with Project 1 on endothelial function and NVC. Because the endothelium and SM function physiologically as one entity, Projects 1 and 2 are inherently highly interdependent. Projects 3 and 4, which focus on dysregulation of cerebrovascular unit function under two divergent, but clinically relevant, pathological conditions, depend on information derived from Projects 1 and 2. The Imaging Core will provide state-of-the-art approaches for Ca2+ measurements in complex systems. The Animal and Instrumentation Core will consolidate and coordinate all animal and in vivo work, including the development of novel genetically encoded ratiometric Ca2+ biosensors. The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease.