MATRIX METALLOPROTEINASE CLEAVAGE OF VERSICAN IN CARDIAC OUTLET REMODELING

心脏出口重塑中 VERSICAN 的基质金属蛋白酶裂解

• 批准号: 8167796
• 负责人: Christine Bruins Kern
• 金额: $ 16.99万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167796
• 关键词: Adult; Aorta; Aortic Rupture; Cardiac; Cardiovascular Diseases; Cardiovascular system; Centers of Research Excellence; Clinical; Computer Retrieval of Information on Scientific Projects Database; Congenital Heart Defects; Connective Tissue; Development; Disease; Disease Progression; Disintegrins; Extracellular Matrix; Family; Funding; Grant; Heart; Homeostasis; Institution; Investigation; Lead; Matrix Metalloproteinases; Metalloproteases; Peptide Hydrolases; Process; Proteoglycan; Pulmonary artery structure; Research; Research Personnel; Resources; Role; Source; United States National Institutes of Health; malformation; programs; versican

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 心脏流出道（OFT）的发育，即：e.主动脉，肺动脉和半月瓣，是一个知之甚少的过程，但OFT畸形占所有先天性心脏缺陷的30%。在发育过程中，普通OFT的富含蛋白多糖的细胞外基质（ECM）被重塑，形成成人心脏的纤维和弹性结缔组织，这一过程最近才开始研究，这也是我的COBRE研究的重点。先前的研究表明，蛋白多糖多功能蛋白聚糖是心脏发育所必需的，并在发育中的心脏出口中显著表达。此外，ECM蛋白酶的ADAMTS（具有血栓形成基序的去整合素和金属蛋白酶）家族对多功能蛋白聚糖的切割发生在心脏出口形成的关键步骤中。 因此，这表明ADAMTS蛋白酶可能是将富含蛋白聚糖的基质重塑为成熟动脉壁和瓣膜的纤维ECM的关键。 重要的是，心血管ECM的异常也导致相对常见的临床表现，如主动脉破裂和粘液瘤性瓣膜病。心血管疾病进展的标志是发育程序的重新表达，包括富含多功能蛋白聚糖的ECM。 考虑到ADAMTS蛋白酶在成人心脏内保持表达的事实，对ADAMTS蛋白酶作用的研究应有助于我们理解心血管ECM的发育和稳态。