Integrin-Matrix Interaction in Cardiovascular Development

描述（由申请人提供）：心血管系统的发展受到复杂的控制，极易受到遗传扰动的影响。最近的研究已经确定了在调节心血管发育中起关键作用的转录因子网络。然而，在这种情况下，关于细胞外基质信号如何控制细胞行为，我们所知甚少。最近，一种基质细胞血管生成蛋白CCN1 （CYR61）在心血管发育中的重要作用已被证实。ccn1缺失小鼠由于血管分叉、血管完整性和房室间隔形态发生受损而导致胚胎死亡。尽管Ccn1小鼠在很大程度上是存活的，但其中20%的小鼠表现出与某些人类先天性心脏病患者相似的房间隔缺陷。Ccn1及其密切同源物Ccn2 （CTGF）的表达在整个心血管发育过程中重叠，与血管疾病和心肌梗死密切相关。然而，Ccn2缺失的小鼠显示骨骼表型而不是心血管表型，这表明Ccn1和Ccn2可能具有重叠的功能。在机制上，CCN蛋白直接与不同的整合素结合，这些整合素已被证明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。本研究旨在验证以下假设，即CCN蛋白的多种功能是其调节血管生成、细胞外基质的合成或组装以及细胞存活或死亡的能力，这些能力依赖于环境。这些概念将在三个具体目标中得到检验。首先，我们将确定CCN1在维持血管结构中的作用，以及CCN1-a？将评估整合素在心血管发展中的相互作用。其次，Ccn1和Ccn2可能的重叠功能将在双重或复合突变体中被剖析。最后，我们将研究CCN蛋白在体外培养的心肌细胞中的凋亡活性，以及CCN1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调节心血管发育提供新的见解，并阐明其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.