Extracellular matrix remodeling and fibrosis

细胞外基质重塑和纤维化

• 批准号: 8413035
• 负责人: JANE M SOTTILE
• 金额: $ 31.31万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413035
• 关键词: Bacterial Adhesins; Blood Vessels; Cardiac; Cardiovascular system; Caveolins; Cell Proliferation; Cells; Choristoma; Cicatrix; Collagen; Collagen Type I; Data; Deposition; Development; Disease; Endocytosis; Event; Excision; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Feedback; Fibroblasts; Fibronectins; Fibrosis; Genetic; Goals; Heart; Heart Block; Heart failure; Homeostasis; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Injury; Integrins; Kidney; Lead; Liver; Lung; MMP14 gene; Matrix Metalloproteinases; Mechanics; Mediating; Membrane; Modeling; Mus; Myocardial; Myocardial Infarction; Normal tissue morphology; Organ; Pathogenesis; Pathologic; Peptides; Phenotype; Play; Process; Property; Proteins; Proteolysis; Publishing; Reagent; Regulation; Reperfusion Injury; Research; Role; Skin; Smooth Muscle Myocytes; Testing; Tissues; Vascular remodeling; base; body system; cell growth; effective therapy; extracellular; heart function; human MMP14 protein; improved; in vivo; inhibitor/antagonist; insight; migration; mouse model; novel; novel strategies; novel therapeutic intervention; polymerization; prevent; receptor; tissue repair; trafficking

DESCRIPTION (provided by applicant): Aberrant extracellular matrix (ECM) remodeling is a hallmark of fibrosis. Fibrosis occurs in multiple organs systems, including the heart. Alterations in the levels, composition, and organization of ECM molecules lead to changes in cell phenotype and altered tissue mechanical properties that contribute to organ function decline. Hence, understanding the underlying mechanisms that contribute to fibrosis is essential for the development of novel therapies that can limit pathologic ECM accumulation. Our data show that the ECM protein fibronectin (FN) is an important regulator of ECM remodeling. Our published data demonstrate that the process of depositing (polymerizing) FN into the ECM regulates the deposition and stability of other ECM molecules, including collagen type I. In addition, agents that we and others have used to inhibit FN polymerization, such as the peptide pUR4, block FN deposition into the ECM, trigger the loss of FN and collagen I fibrils, enhance FN and collagen I endocytosis, and inhibit inflammation. Our data show that removal of FN and collagen I from the ECM is a coordinated process that involves MT1-MMP (membrane type 1 matrix metalloproteinase) mediated extracellular degradation, followed by 1521 integrin-mediated endocytosis. Further, our preliminary data demonstrate that 1521 endocytosis is regulated by both fibronectin polymerization and MT1-MMP. These data suggest that integrin-mediated endocytosis is a major regulator of ECM remodeling, and that agents that regulate ECM endocytosis may provide a novel approach to limiting pathologic ECM accumulation. Importantly, our in vivo data show that the FN polymerization inhibitor pUR4 effectively blocks the accumulation of ECM FN and collagen I and reduces inflammation in a mouse vascular injury model. Further, our preliminary data show that pUR4 blocks fibrosis and improves cardiac function in a mouse model of myocardial infarction (MI). These data are the first to show that FN is a major contributor to adverse ECM remodeling in the cardiovascular system, and that blocking FN deposition may be an effective strategy to limit excess accumulation of ECM and inhibit inflammation during fibrosis. In this application, we will test the hypothesis that FN polymerization and MT1-MMP play key roles in regulating ECM remodeling by controlling 21 integrin endocytosis, and that regulation of ECM endocytosis is a key mechanism that limits ECM accumulation. We will also test the hypothesis that FN polymerization regulates the development of cardiac fibrosis by modulating the pro-inflammatory accumulation of FN and collagen I. These studies may lead to the development a new therapeutic approach for limiting fibrosis, for which there are few effective treatments.

描述（由申请人提供）：异常细胞外基质（ECM）重塑是纤维化的标志。纤维化发生在多个器官系统，包括心脏。ECM分子水平、组成和组织的改变会导致细胞表型的改变和组织力学特性的改变，从而导致器官功能的下降。因此，了解导致纤维化的潜在机制对于开发能够限制病理性ECM积累的新疗法至关重要。我们的数据表明，ECM蛋白纤维连接蛋白（FN）是ECM重塑的重要调节因子。我们发表的数据表明，FN沉积（聚合）到ECM中的过程调节了其他ECM分子的沉积和稳定性，包括I型胶原。此外，我们和其他人用来抑制FN聚合的药物，如肽pUR4，可以阻止FN沉积到ECM中，引发FN和I型胶原原纤维的损失，增强FN和I型胶原的内吞作用，并抑制炎症。我们的数据表明，从ECM中去除FN和胶原I是一个协调的过程，包括MT1-MMP（膜型1基质金属蛋白酶）介导的细胞外降解，然后是1521整合素介导的内吞作用。此外，我们的初步数据表明，1521内吞作用受到纤维连接蛋白聚合和MT1-MMP的调节。这些数据表明，整合素介导的内吞作用是ECM重塑的主要调节因子，而调节ECM内吞作用的药物可能为限制病理性ECM积累提供了一种新的途径。重要的是，我们的体内数据表明，在小鼠血管损伤模型中，FN聚合抑制剂pUR4有效地阻断ECM FN和胶原I的积累，并减少炎症。此外，我们的初步数据显示，pUR4在心肌梗死（MI）小鼠模型中阻断纤维化并改善心功能。这些数据首次表明，FN是心血管系统中不良ECM重塑的主要因素，阻断FN沉积可能是限制ECM过度积累和抑制纤维化期间炎症的有效策略。在本应用中，我们将验证FN聚合和MT1-MMP通过控制21整合素内吞作用在调节ECM重塑中发挥关键作用的假设，以及ECM内吞作用的调节是限制ECM积累的关键机制。我们还将验证FN聚合通过调节FN和胶原i的促炎积累来调节心脏纤维化发展的假设。这些研究可能会导致开发一种新的治疗方法来限制纤维化，目前还没有有效的治疗方法。