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

• 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
• 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

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.

项目摘要/摘要 哺乳动物心脏在缺血性心脏损伤后再生能力较差，并通过疤痕愈合 队形。多项临床研究表明，疤痕组织的大小是一种独立的预测因子 急性心肌梗死后的心血管结局和死亡率。然而，人们对此知之甚少。 调节急性缺血性心脏损伤后纤维化程度或瘢痕组织大小的因素。胶原蛋白 是缺血性心脏损伤后差异表达最高的基因，并且仍然是最丰富的 梗塞心脏中分泌的细胞外基质(ECM)蛋白的形式。I型和III型胶原是 心脏中发现了主要的胶原蛋白，但我们发现大量的胶原蛋白是最低限度的 在未受损伤的心脏中表达是在缺血性心脏损伤后强烈诱导的。在这项提案中，我们 研究胶原异质性的生理必要性，并证明V型胶原，a 纤维性胶原在调节缺血性心脏损伤后瘢痕组织的大小中起着关键作用。vbl.使用 RNA-FISH(荧光原位杂交)或MerFish的多路复用，我们创建了 并利用遗传功能丧失技术确定V型胶原在心脏疾病中的功能意义 调节梗死后瘢痕组织的大小和心功能。我们确定化学成分是如何 V型胶原缺失后细胞外基质的变化，研究改变的基质的力学-生物学特性 并研究这些变化如何影响心功能和心肌壁应力的分布。我们解剖 V型胶原调节瘢痕大小的分子机制。我们证明了类型V 心肌梗死后心肌成纤维细胞的深度活化与胶原缺失有关 心肌细胞整合素表达谱改变继发于肌成纤维细胞激活增强 成纤维细胞。我们研究了整合素表达改变的机制，整合素介导的驱动机制 并确定抑制特定整合素是否可以挽救表型 在V型胶原缺乏状态下观察到梗死后瘢痕形成增加。综上所述，我们的建议将 使我们对心脏创伤愈合有更广泛的理解，并说明心脏修复的新范式 心脏疤痕的结构成分控制着疤痕本身的大小。