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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：
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
项目类别：
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

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.

项目总结