Multi-Scale Modeling of Vascular Signaling Units

项目摘要 动脉的功能是输送维持生命功能和生存所必需的氧气和营养物质。 体内的细胞。动脉直径是血液流动的关键决定因素，动脉直径受血管收缩状态的微调。 排列在这些血管壁上的平滑肌细胞。然而，到目前为止，动脉的肌源性控制模型 肌张力在很大程度上是基于男性肌细胞的数据。然而，我们团队的最新数据 提示决定动脉肌细胞运作的性别特异性特征可归因于差异 在PKC锚定蛋白AKAP150和CaV1.2形成的信号复合体的空间组织中 通道，以及它们调节平滑肌收缩能力的方式。我们的发现挑战了这位将军 基于以下数据的生肌反应的电学和药理学控制模型的适用性 并支持男性和女性肌源性反应受到不同调控的观点 动脉。在这个项目中，我们实施了一种多尺度系统方法，包括超分辨率成像， 严格研究血液控制机制的电生理学和计算方法 生理和病理条件下流经男性和女性软脑膜-实质循环单位 条件。具体目标1是建立基本的性别特异性机制，通过 CaV1.2通道存在于血管平滑肌中。具体目标2是确定物理的影响 血管紧张素Ⅱ受体1、AKAP150、PKCα和CaV1.2通道在心肌细胞肌源性张力中的作用 男性和女性动脉平滑肌。最后，在具体目标3中，我们将调查 CaV1.2和AngIIR1AKAP150/PKCα信号单位的数量和分子组成的差异 男性和女性发育过程中的钙内流、动脉壁[Ca~(2+)]i和肌源性张力 高血压的症状。这项工作将导致第一个结合性别的血管平滑肌功能模型- 在健康和疾病期间，蛋白质组织、电活动和钙信号的特定变化，这 可为制定合理的男性和女性高血压治疗策略提供参考。

Project Summary The function of arteries is to deliver oxygen and nutrients necessary to sustain the function and survival of every cell in the body. Arterial diameter, a key determinant of blood flow, is finely tuned by the contractile state of the smooth muscle cells lining the walls of these vessels. To date, however, models of myogenic control of arterial smooth muscle tone have largely been based on data from male myocytes. Yet, recent data from our team suggest that sex-specific features that determine the operation of arterial myocytes are attributable to differences in the spatial organization of signaling complexes formed by the PKC-anchoring protein AKAP150 and CaV1.2 channels, and the manner in which they regulate smooth muscle contractility. Our findings challenge the general applicability of a model for electrical and pharmacological control of the myogenic response based on data from male myocytes and support the view that myogenic responses are differentially regulated in male and female arteries. In this project, we implement a multi-scale systems approach that includes super-resolution imaging, electrophysiology, and computational approaches to rigorously investigate the mechanisms controlling blood flow through the male and female pial-parenchymal circulatory unit under physiological and pathological conditions. Specific aim 1 is to establish the fundamental sex-specific mechanisms controlling Ca2+ influx via CaV1.2 channels in vascular smooth muscle. Specific aim 2 is to determine the impact of the physical organization of type 1 AngII receptors (AngIIR1), AKAP150, PKCα, and CaV1.2 channels on myogenic tone in male and female arterial smooth muscle. Finally, in specific aim 3 we will investigate whether changes in the number and molecular organization of CaV1.2 and AngIIR1/AKAP150/PKCα signaling units differentially alter Ca2+ influx, arterial wall [Ca2+]i, and myogenic tone in male and female smooth muscle during the development of hypertension. This work will lead to the first model of vascular smooth muscle function that incorporates sex- specific variations in protein organization, electrical activity, and Ca2+ signaling during health and disease, which could inform the development of rational strategies for the treatment of hypertension in male and female.