MATRIX METALLOPROTEINASE CLEAVAGE OF VERSICAN IN CARDIAC OUTLET REMODELING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 心脏流出道(OFT)的发育，即主动脉、肺动脉和半月瓣，是一个鲜为人知的过程，但OFT畸形占所有先天性心脏缺陷的30%。在发育过程中，普通心脏的富含蛋白多糖的细胞外基质(ECM)被重塑以形成成人心脏的纤维和弹性结缔组织的过程最近才开始被研究，这是我的Cobre研究的重点。先前的研究表明，蛋白多聚糖对心脏发育是必不可少的，并在发育中的心脏出口显著表达。此外，在心脏出口形成的关键步骤中，ECM蛋白水解酶家族ADAMTS(具有血栓反应蛋白基序的去整合素和金属蛋白酶)对VERSICAN的切割也是重要的。因此，这提示ADAMTS蛋白水解酶可能在成熟动脉壁和瓣膜的纤维状ECM中重塑富含蛋白多糖的基质中起关键作用。重要的是，心血管ECM的异常也会导致相对常见的临床表现，如主动脉破裂和粘液瘤瓣膜病。心血管疾病进展的一个标志是发育程序的重新表达，包括富含维西肯的ECM。考虑到ADAMTS蛋白水解酶在成人心脏中维持表达的事实，研究ADAMTS蛋白水解酶的作用将有助于我们理解心血管ECM的发育和稳态。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of the cardiac outflow tract (OFT), i. e. aorta, pulmonary artery and semi-lunar valves, is a poorly understood process yet OFT malformations constitute 30% of all congenital heart defects. The process by which the proteoglycan-rich extracellular matrix (ECM) of the common OFT is remodeled during development to form the fibrous and elastic connective tissues of the adult heart has only recently begun to be investigated and is the focus of my COBRE research. Previous studies have shown that the proteoglycan versican is essential for cardiac development and is prominently expressed in the developing cardiac outlet. Furthermore the cleavage of versican by the ADAMTS (A Disintegrin and Metalloproteinase with ThromboSpondin motifs) family of ECM proteinases occurs in key steps of cardiac outlet formation. Therefore this suggests that ADAMTS proteinases may be critical for remodeling of the proteoglycan rich matrix into the fibrous ECM of the mature arterial wall and valves. Importantly, anomalies of the cardiovascular ECM also lead to relatively common clinical manifestations such as aortic rupture and myxomatous valve disease. A hallmark of cardiovascular disease progression is the re-expression of developmental programs including an ECM rich in versican. Taken together with the fact that ADAMTS proteinases maintain expression within the adult heart, investigation into the role of ADAMTS proteinases should contribute to our understanding of both development and homeostasis of the cardiovascular ECM.