Multi-Scale Modeling of Vascular Signaling Units

血管信号单元的多尺度建模

• 批准号: 10614418
• 负责人: COLLEEN E CLANCY
• 金额: $ 54.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614418
• 关键词: Address; Angiotensin II; Angiotensin II Receptor; Arteries; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Line; Cells; Cessation of life; Communities; Complex; Computer Models; Contracts; Coupled; Coupling; Data; Dependence; Development; Diameter; Diglycerides; Dihydropyridines; Disease; Electrophysiology (science); Event; Experimental Models; Female; G alpha q Protein; General Population; Goals; Health; Hypertension; Inositol; Link; Medical; Membrane; Mesentery; Modeling; Molecular; Muscle Cells; Muscle Tonus; Muscle function; Nutrient; Oxygen; PRKCA gene; Pathologic; Patients; Permeability; Pharmaceutical Preparations; Physiologic pulse; Physiological; Protein Kinase; Proteins; Receptor Signaling; Receptor, Angiotensin, Type 1; Regulation; Sarcoplasmic Reticulum; Sex Differences; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; System; Testing; Variant; Vascular Smooth Muscle; Woman; Work; blood pressure control; blood pressure regulation; cardiovascular risk factor; experimental study; hypertension treatment; hypertensive; inorganic phosphate; male; men; models and simulation; modifiable risk; mortality; multi-scale modeling; nano; nanometer; nanometer resolution; novel; novel strategies; operation; pharmacologic; premature; prevent; protein structure; receptor; response; sex; superresolution imaging; treatment strategy; voltage

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.

项目概要 动脉的功能是输送维持每个器官的功能和生存所需的氧气和营养物质。 体内的细胞。动脉直径是血流的关键决定因素，可通过动脉的收缩状态进行微调。 平滑肌细胞排列在这些血管壁上。然而，迄今为止，动脉生肌控制模型 平滑肌张力很大程度上基于男性肌细胞的数据。然而，我们团队的最新数据 表明决定动脉肌细胞运作的性别特异性特征可归因于差异 参与由 PKC 锚定蛋白 AKAP150 和 CaV1.2 形成的信号复合物的空间组织 通道，以及它们调节平滑肌收缩性的方式。我们的发现挑战了普遍的看法 基于数据的生肌反应的电学和药理学控制模型的适用性 男性肌细胞并支持以下观点：男性和女性的生肌反应受到不同的调节 动脉。在这个项目中，我们实现了一种多尺度系统方法，包括超分辨率成像、 电生理学和计算方法来严格研究控制血液的机制 生理和病理状态下流经男性和女性软脑膜实质循环单位 状况。具体目标 1 是建立控制 Ca2+ 流入的基本性别特异性机制 血管平滑肌中的 CaV1.2 通道。具体目标 2 是确定物理影响 1 型 AngII 受体 (AngIIR1)、AKAP150、PKCα 和 CaV1.2 通道对肌源性张力的影响 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 AngIIR1/AKAP150/PKCα 信号单元的数量和分子结构存在差异 发育过程中雄性和雌性平滑肌的 Ca2+ 流入、动脉壁 [Ca2+]i 和肌源张力 高血压。这项工作将导致第一个结合性别的血管平滑肌功能模型 健康和疾病期间蛋白质组织、电活动和 Ca2+ 信号传导的特定变化， 可以为制定治疗男性和女性高血压的合理策略提供信息。