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，重点是脑内实质 小动脉，它在大脑内分布血液，并显示出独特的属性，尽管人们对此知之甚少。 总的目标是阐明血管内皮细胞和平滑肌细胞 实质小动脉(PAS)正常调节血管张力和神经血管偶联(NVC)， 缺血/再灌注(L/R)损伤和蛛网膜下腔出血(SAH)。中央统一 主题是在组成脑血管单位的细胞中对钙信号的精确控制？ 内皮、SM和星形胶质细胞决定正常的脑功能；延伸到钙的功能障碍 信号动力学在脑血管疾病中起作用。每个项目都研究重叠的元素 形成一个整体的生物系统。项目1将提供有关属性和功能的第一批信息 PA内皮细胞(ECs)，探索Ca^*信号和对Ca^*敏感的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 电压依赖性钙通道(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互动，探索 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EC-SM离子通道功能的变化。项目4，重点是PAS和 在SAH之后的NVC，与关于SAH对SM Cav和Trp通道的影响的项目2交叉，并与 关于内皮功能和NVC的项目1。因为内皮细胞和SM在生理上是一体的 实体、项目1和项目2本质上高度相互依赖。项目3和项目4，重点是监管失调 脑血管单位功能在两种不同的情况下，但临床相关的病理情况，取决于 来自项目1和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。动物和仪器核心将整合和 协调所有动物和体内工作，包括开发新的基因编码、比率测定 CA^*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，以及 通过这样做，揭示了可以在脑血管治疗中开发的令人兴奋的新靶点 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.