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，重点是脑实质（脑内）小动脉，它在大脑中分配血液，并表现出独特的，尽管知之甚少的特性。本研究的目的是阐明脑缺血/再灌注（I/R）损伤和蛛网膜下腔出血（SAH）后，脑实质小动脉（PA）的内皮和平滑肌（SM）调节血管张力和神经血管偶联（NVC）的分子机制。中心统一的主题是，在细胞组成的“脑血管单位”-内皮细胞，SM和星形胶质细胞的Ca 2+信号的精确控制决定正常的脑功能;通过扩展，功能障碍的Ca 2+信号动力学有助于脑血管疾病。每个项目研究生物系统的重叠元素，形成一个整体。项目1将提供有关PA内皮细胞（EC）特性和功能的第一批信息，探索Ca 2+信号传导和Ca 2+敏感的SK和IK钾通道及其对SM功能和NVC的影响。项目2将重点关注实质小动脉SM，重点是电压依赖性Ca 2+通道（Cav）和瞬时受体电位（TRP）通道。项目1和项目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相互作用，以探索I/R后实质小动脉反应性发生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SAH后的PA和NVC，与项目2相交于SAH对SM Cav和TRP通道的影响，与项目1相交于内皮功能和NVC。因为内皮和SM作为一个实体在生理上起作用，所以项目1和项目2内在地高度相互依赖。项目3和项目4侧重于在两种不同但临床相关的病理条件下脑血管单位功能失调，依赖于项目1和项目2的信息。Imaging Core将为复杂系统中的Ca 2+测量提供最先进的方法。动物和仪器的核心将巩固和协调所有的动物和体内工作，包括新的基因编码的比率钙生物传感器的发展。长期目标是了解健康和疾病中大脑的血流，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.