Calcium signaling in the cerebrovascular unit in health and disease

该计划包括四个项目和三个核心，重点是脑实质（脑内） 微动脉，它在大脑中分配血液，并表现出独特的，尽管知之甚少的性质。 总的目标是阐明内皮和平滑肌 (SM)实质小动脉（PA）的正常调节血管张力和神经血管耦联（NVC）， 以及在缺血/再灌注（I/R）损伤和蛛网膜下腔出血（SAH）之后。中央统一 主题是精确控制构成“脑血管单元”的细胞中的Ca^* 信号传导。 内皮细胞、SM和星形胶质细胞决定着正常的脑功能;通过扩展，Ca^* 信号动力学导致脑血管疾病。每个项目都研究了 生物系统形成一个整体。项目1将提供有关性能和功能的第一个信息， PA内皮细胞（EC），探索Ca^* 信号传导和Ca^* 敏感性SK和IK钾通道， 它们对SM功能和NVC的影响。项目2将侧重于实质小动脉SM，重点是 电压依赖性Ca^* 通道（Cav）和瞬时受体电位（TRP）通道。项目1和2 为项目3和项目4提供平台。项目3将与项目1和项目2互动， 实质小动脉反应性发生深刻变化的潜在机制基础， I/R后，重点关注离子通道功能的EC-SM变化。项目4，侧重于保护区， SAH后的NVC与关于SAH对SM Cav和TRP通道的影响的项目2交叉，并且与 内皮功能和NVC项目1。因为内皮和平滑肌在生理上是一体的 项目1和项目2在本质上是高度相互依存的。项目3和项目4，重点是失调 脑血管单位功能在两个不同的，但临床相关的病理条件下，取决于 项目1和项目2的信息。成像核心将提供最先进的方法， 复杂系统中的Ca^* 测量。动物和仪器核心将巩固和 协调所有动物和体内工作，包括开发新的遗传编码，比例 钙生物传感器。长期目标是了解健康和疾病情况下大脑的血流，以及 通过这样做，揭示了令人兴奋的新靶点，可用于治疗脑血管疾病， 疾病

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 Ca^* signaling in cells composing the "cerebrovascular unit"¿ endothelium, SM and astrocytes¿determines normal brain function; by extension, dysfunction of Ca^* 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 Ca^* signaling and Ca^*-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 Ca^* 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 Ca^* 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 Ca^* 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.