Integrin-Matrix Interaction in Cardiovascular Development

描述（由申请人提供）：心血管系统的发育处于复杂的控制之下，对遗传干扰高度敏感。最近的研究已经确定了一个转录因子网络，这些转录因子在调节心血管发育方面发挥着关键作用。然而，关于细胞外基质信号如何在这种情况下控制细胞行为的知之甚少。CCN 1（CYR 61），一种基质细胞血管生成蛋白，在心血管发育中的重要作用最近已被确定。ccn 1基因敲除小鼠由于血管分叉、血管完整性和房室瓣间隔形态发生受损而遭受胚胎死亡。虽然Ccn 1小鼠在很大程度上是可行的，但其中20%的小鼠表现出类似于在一些人类先天性心脏病患者中发现的房间隔缺损。Ccn 1及其同源物Ccn 2（CTGF）在心血管发育过程中的表达是重叠的，与心血管疾病和心肌梗死密切相关。然而，Ccn 2-null小鼠显示骨骼而不是心血管表型，表明Ccn 1和Ccn 2可能具有重叠的功能。在机制上，CCN蛋白直接结合不同的整合素，其已显示在细胞培养系统中介导各种CCN活性。然而，整合素在体内CCN蛋白功能中的作用尚不清楚。该提议试图检验以下假设：CCN蛋白的不同功能的基础是它们以环境依赖性方式调节血管生成、细胞外基质的合成或组装以及细胞存活或细胞死亡的能力。这些概念将在三个具体目标中得到检验。首先，CCN 1在维持血管结构中的作用将被确定，CCN 1-a？将评估心血管发育中整联蛋白相互作用。第二，Ccn 1和Ccn 2可能的重叠功能将在双重或复合突变体中进行解剖。最后，将研究CCN蛋白在培养的心肌细胞中的凋亡活性，以及CCN 1在心肌梗死后心肌细胞凋亡中的作用。总之，这些研究将为CCN蛋白如何通过细胞外基质信号传导调节心血管发育提供新的见解，并阐明它们在心血管疾病中的作用。

DESCRIPTION (provided by applicant): Development of the cardiovascular system is under complex control and is highly susceptible to genetic perturbations. Recent studies have identified a network of transcription factors that play critical roles in regulating cardiovascular development. Far less is known, however, about how extracellular matrix signaling controls cell behavior in this context. The essential role of CCN1 (CYR61), a matricellular angiogenic protein, in cardiovascular development has been recently established. Ccn1-null mice suffer embryonic death due to impaired vessel bifurcation, vessel integrity, and atrioventricular valvuoseptal morphogenesis. Although Ccn1 mice are largely viable, 20% of them exhibit atrial septal defects similar to those found in some patients with human congenital heart disease. The expression of Ccn1 and its close homologue Ccn2 (CTGF) is overlapping throughout cardiovascular development, and tightly associated with vascular diseases and myocardial infarction. However, Ccn2-null mice show skeletal rather than cardiovascular phenotypes, suggesting that Ccn1 and Ccn2 may serve overlapping functions. Mechanistically, CCN proteins bind directly to distinct integrins, which have been shown to mediate various CCN activities in cell culture systems. However, the role of integrins in CCN proteins function in vivo is unknown. This proposal seeks to test the hypothesis that underlying the diverse functions of CCN proteins are their ability to regulate angiogenesis, the synthesis or assembly of the extracellular matrix, and cell survival or cell death in a context dependent manner. These notions will be tested in three specific aims. First, the role of CCN1 in maintaining vascular structure will be determined, and the contribution of CCN1-a? integrin interaction in cardiovascular development will be assessed. Second, the possible overlapping functions of Ccn1 and Ccn2 will be dissected in double or compound mutants. Finally, the apoptotic activities of CCN proteins in cultured cardiomyocytes will be investigated, as will the role of CCN1 in cardiomyocyte apoptosis after myocardial infarction. Together, these studies will provide novel insights into how CCN proteins regulate cardiovascular development through extracellular matrix signaling, and shed light on their roles in cardiovascular diseases.