Multi-Scale Modeling of Vascular Signaling Units

血管信号单元的多尺度建模

基本信息

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
项目类别：
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

项目摘要

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。体内细胞的动脉直径是血流的关键决定因素，由细胞的收缩状态进行微调。然而，迄今为止，还没有动脉肌源性控制的模型。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我们的研究结果挑战了一般观点。基于数据的生肌反应的电学和药理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、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具体目标 1 是建立控制 Ca2+ 流入的基本性别特异性机制。具体目标2是确定CaV1.2通道对身体的影响。 1 型 AngII 受体 (AngIIR1)、AKAP150、PKCα 和 CaV1.2 通道对肌源性张力的影响最后，在具体目标 3 中，我们将研究男性和女性动脉平滑肌是否发生变化。 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。