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Role of collagen heterogeneity in remodeling of acute and chronic heart scars

胶原异质性在急慢性心脏疤痕重塑中的作用

基本信息

批准号：
10439439
负责人：
Arjun Deb
金额：
$ 50.7万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439439
关键词：
Acute Acute myocardial infarction Affect Animals Atomic Force Microscopy Automobile Driving Biological Biomedical Engineering Cardiac Cardiac health Cardiovascular system Cells Chemicals Chronic Cicatrix Clinical Research Collagen Collagen Fibril Collagen Type III Collagen Type V Data Dilatation - action Extracellular Matrix Extracellular Matrix Proteins Family Fibrillar Collagen Fibroblasts Fibrosis Fishes Fluorescent in Situ Hybridization Gene Expression Genes Genetic Heart Heart Injuries Heterogeneity Individual Infarction Integrins Maps Mechanics Mediating Minor Molecular Mus Myocardial Myocardial Infarction Myocardium Myofibroblast Natural regeneration Outcome Patients Phenotype Physiological Play Property Proteomics Public Health RNA Regulation Role Secondary to Signal Transduction Smooth Muscle Stress Techniques Therapeutic Tissues Transmission Electron Microscopy Ventricular Remodeling cardiac repair healing heart dimension/size heart function heart imaging hemodynamics in vivo ischemic injury loss of function mechanical properties mortality novel pressure repaired response spatiotemporal tissue support frame transcriptomics wound healing

项目摘要

Project Summary/Abstract The mammalian heart possesses a poor ability to regenerate after ischemic cardiac injury and heals via scar formation. Multiple clinical studies have demonstrated that the size of scar tissue is an independent predictor of cardiovascular outcomes and mortality after acute myocardial infarction. However, little is understood about factors that regulate the degree of fibrosis or size of scar tissue after acute ischemic cardiac injury. Collagens are the most differentially upregulated genes following ischemic cardiac injury and remain the most abundant form of extracellular matrix (ECM) proteins secreted in the infarcted heart. Type I and III collagens are the principal collagens found in the heart but we show that a large number of collagens that are minimally expressed in the uninjured heart are robustly induced following ischemic cardiac injury. In this proposal, we investigate the physiological necessity of collagen heterogeneity and demonstrate that type V collagen, a fibrillar collagen plays a critical role in regulating the size of scar tissue after ischemic cardiac injury. Using multiplexing of RNA-FISH (fluorescence in situ hybridization) or MERFISH, we create a collagen map of the heart and use genetic loss of function techniques to determine the functional significance of type V collagen in regulating the size of post infarct scar tissue and heart function. We determine how the chemical composition of ECM changes following type V collagen deletion, study the mechano-biological properties of altered matrix and examine how such changes affect cardiac function and distribution of myocardial wall stress. We dissect the molecular mechanisms mediating regulation of scar size by type V collagen. We demonstrate that type V collagen deletion is associated with profound activation of cardiac fibroblasts in the infarcted heart and show that augmented myofibroblast activation is secondary to an altered integrin expression profile on cardiac fibroblasts. We study the mechanisms of altered integrin expression, integrin mediated mechanisms driving myofibroblast activation and determine whether inhibition of specific integrins can rescue the phenotype of increased post infarct scarring observed in type V collagen deficient states. Taken together, our proposal will lead to a broader understanding of cardiac wound healing and illustrate a new paradigm of cardiac repair where the structural constituents of heart scars regulate the size of scar itself.

项目总结/文摘