Extracellular matrix remodeling and fibrosis

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中，包括心脏。ECM分子的水平、组成和组织的改变导致细胞表型的改变和组织机械性质的改变，这有助于器官功能下降。因此，了解导致纤维化的潜在机制对于开发可以限制病理性ECM积累的新疗法至关重要。我们的数据表明，ECM蛋白纤连蛋白（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中的过程调节其他ECM分子（包括I型胶原）的沉积和稳定性。此外，我们和其他人已经使用的抑制FN聚合的试剂，如肽pUR 4，阻断FN沉积到ECM中，引发FN和胶原蛋白I原纤维的损失，增强FN和胶原蛋白I内吞作用，并抑制炎症。我们的数据表明，从ECM中去除FN和胶原蛋白I是一个协调的过程，涉及MT 1-MMP（膜1型基质金属蛋白酶）介导的细胞外降解，随后是1521整合素介导的内吞作用。此外，我们的初步数据表明，1521内吞作用是由纤连蛋白聚合和MT 1-MMP。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，并且调节ECM内吞作用的试剂可以提供限制病理性ECM积累的新方法。重要的是，我们的体内数据表明，FN聚合抑制剂pUR 4有效地阻断了ECM FN和胶原蛋白I的积累，并减少了小鼠血管损伤模型中的炎症。此外，我们的初步数据显示，pUR 4阻断心肌梗死（MI）小鼠模型中的纤维化并改善心脏功能。这些数据首次表明FN是心血管系统中不良ECM重塑的主要贡献者，并且阻断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。在本申请中，我们将检验以下假设：FN聚合和MT 1-MMP通过控制21整合素内吞作用在调节ECM重塑中起关键作用，并且ECM内吞作用的调节是限制ECM积累的关键机制。我们还将检验FN聚合通过调节FN和胶原I的促炎性积聚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，对此几乎没有有效的治疗方法。

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.