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.

项目概要/摘要 哺乳动物心脏在缺血性心脏损伤后再生能力较差，只能通过疤痕愈合 形成。多项临床研究表明，疤痕组织的大小是一个独立的预测因子。 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疤痕组织大小的因素。胶原蛋白 是缺血性心脏损伤后差异最大的上调基因，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 型胶原蛋白是 主要的胶原蛋白存在于心脏中，但我们发现大量的胶原蛋白最少 在未受伤的心脏中表达在缺血性心脏损伤后被强烈诱导。在这个提案中，我们 研究胶原蛋白异质性的生理必要性并证明 V 型胶原蛋白 纤维状胶原在调节缺血性心脏损伤后疤痕组织的大小中起着至关重要的作用。使用 通过 RNA-FISH（荧光原位杂交）或 MERFISH 的多重分析，我们创建了 心脏并使用遗传功能丧失技术来确定 V 型胶原蛋白在心脏中的功能意义 调节梗塞后疤痕组织的大小和心脏功能。我们如何确定化学成分 V 型胶原缺失后 ECM 变化的研究，研究改变基质的机械生物学特性 并检查这些变化如何影响心脏功能和心肌壁应力的分布。我们剖析 V 型胶原介导调节疤痕大小的分子机制。我们证明V型 胶原蛋白缺失与梗塞心脏中心肌成纤维细胞的深度激活有关，并显示 心肌成纤维细胞活化增强是继发于心肌细胞整合素表达谱改变的 成纤维细胞。我们研究整合素表达改变的机制，整合素介导的驱动机制 肌成纤维细胞激活并确定特定整合素的抑制是否可以挽救肌成纤维细胞的表型 在 V 型胶原缺乏状态下观察到梗死后疤痕增加。总而言之，我们的建议将 导致对心脏伤口愈合的更广泛理解并阐明心脏修复的新范例 心脏疤痕的结构成分调节疤痕本身的大小。