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 动脉的功能是输送维持每个人的功能和生存所必需的氧气和营养物质。 细胞在体内。动脉直径是血流的一个关键决定因素，它是通过血管的收缩状态来微调的。 平滑肌细胞排列在血管壁上。然而，到目前为止，肌源性控制动脉的模型 平滑肌张力主要基于来自雄性肌细胞数据。然而，我们团队最近的数据显示， 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 PKC锚定蛋白AKAP 150和CaV 1.2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 基于来自以下数据的生肌反应的电和药理学控制模型的适用性： 男性肌细胞并支持男性和女性肌源性反应受到差异调节的观点 动脉在这个项目中，我们实现了一个多尺度系统的方法，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 在生理和病理条件下，通过男性和女性软脑膜实质循环单元的流量 条件具体目标1是建立基本的性别特异性机制控制钙离子内流，通过 血管平滑肌中的CaV1.2通道。具体目标2是确定物理影响 1型血管紧张素Ⅱ受体（AngIIR 1）、AKAP 150、PKCα和CaV1.2通道在肌源性紧张度中的组织化 男性和女性动脉平滑肌。最后，在具体目标3中，我们将研究 CaV1.2和AngIIR 1/AKAP 150/PKCα信号单位的数量和分子结构差异改变 发育过程中雄性和雌性平滑肌的Ca ~（2+）内流、动脉壁[Ca ~（2+）]i和肌源性张力 高血压这项工作将导致第一个模型的血管平滑肌功能，纳入性别- 在健康和疾病期间蛋白质组织、电活动和Ca 2+信号传导的特定变化， 可为男性和女性高血压的合理治疗策略的制定提供信息。