Multi-Scale Modeling of Vascular Signaling Units

血管信号单元的多尺度建模

• 批准号: 10394236
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394236
• 关键词: Address; Angiotensin II; Angiotensin II Receptor; Arteries; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Cells; Cessation of life; Communities; Complex; Computer Models; Contracts; Coupled; Coupling; Data; Dependence; Development; Diglycerides; Dihydropyridines; Disease; Electrophysiology (science); Event; Experimental Models; Female; G alpha q Protein; General Population; Goals; Health; Hypertension; Image; Inositol; Lead; Link; Mechanics; Medical; Membrane; Mesentery; Modeling; Molecular; Muscle Cells; Muscle Tonus; Muscle function; Nutrient; Oxygen; PRKCA gene; Pathologic; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Physiological; Protein Kinase; Proteins; Receptor, Angiotensin, Type 1; Regulation; Resolution; Sarcoplasmic Reticulum; Sex Differences; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; System; Testing; Variant; Vascular Smooth Muscle; Woman; Work; base; blood pressure control; blood pressure regulation; cardiovascular risk factor; experimental study; hypertension treatment; hypertensive; male; men; models and simulation; modifiable risk; mortality; multi-scale modeling; nano; nanometer; nanometer resolution; novel; novel strategies; operation; premature; prevent; protein structure; receptor; response; sex; 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.

项目摘要 动脉的功能是提供维持每个人的功能和生存所必需的氧气和营养 细胞在体内。动脉直径是血流确定的钥匙，由收缩状态进行精细调节 平滑肌细胞在这些容器的壁上衬里。然而，迄今为止，动脉肌原性控制模型 平滑肌张力主要基于雄性肌细胞的数据。但是，我们团队的最新数据 建议确定动脉肌细胞操作的性别特异性特征归因于差异 在由PKC锚定蛋白AKAP150和CAV1.2形成的信号复合物的空间组织中 通道，以及它们调节平滑肌肉收缩力的方式。我们的发现挑战了一般 基于数据的数据适用于肌原反应的电气和药物控制 雄性肌细胞并支持男性和女性肌源性反应不同的观点 动脉。在这个项目中，我们实施了一种多尺度系统方法，其中包括超分辨率成像， 电生理学和计算方法严格研究控制血液的机制 在生理和病理学下，流过男性和女性雌性帕尔 - 辅助电路单位 状况。特定目的1是建立控制Ca2+影响的基本性别特异性机制 Cav1.2血管平滑肌中的通道。特定目标2是确定物理的影响 1型AngII受体（Angiir1），AKAP150，PKCα和CAV1.2通道的组织在肌原态上 雄性和雌性动脉平滑肌。最后，在特定目标3中，我们将调查是否改变 CAV1.2和Angiir1/AKAP150/PKCα信号单元的数量和分子组织不同改变 CA2+影响，动脉壁[Ca2+] I和在发育过程中男性和女性平滑肌中的肌吻合语气 高血压。这项工作将导致首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+信号的特定变化， 可以告知男女治疗高血压的理性策略的发展。