Integrin-Matrix Interaction in Cardiovascular Development

心血管发育中的整合素-基质相互作用

• 批准号: 7211033
• 负责人: LESTER F LAU
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211033
• 关键词: Adult; Angiogenic Proteins; Animals; Apoptosis; Apoptotic; Atrial Heart Septal Defects; Binding; Blood Vessels; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cell Culture System; Cell Death; Cell Survival; Cells; Cessation of life; Complement; Complex; Development; Embryo; Exhibits; Extracellular Matrix; Family member; Gene Expression; Genetic; Heart; Homologous Gene; Human; Inflammation; Integrins; Knockout Mice; Light; Location; Maps; Mediating; Molecular; Morphogenesis; Mus; Myocardial Infarction; Nature; Patients; Phenotype; Placenta; Play; Protein Binding; Proteins; Regulation; Role; Ruptured Aneurysm; Signal Transduction; Signaling Protein; Skeletal system; Smooth Muscle Myocytes; Structure; Susceptibility Gene; Testing; Thinking; Tissues; Tumor Necrosis Factor Ligand Superfamily Member 6; Vascular Diseases; angiogenesis; atrioventricular septal defect; cell behavior; cell type; congenital heart disorder; connective tissue growth factor; cysteine rich protein; dosage; extracellular; in vivo; injury and repair; insight; migration; mutant; novel; protein function; receptor; response to injury; transcription factor

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.

描述(由申请人提供)：心血管系统的发育受到复杂的控制，并且对遗传扰动非常敏感。最近的研究发现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，我们知道的要少得多。CCN1(CYR61)，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被证实。CCN1基因缺失的小鼠因血管分叉、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CCN1小鼠在很大程度上是存活的，但其中20%的小鼠表现出类似于一些人类先天性心脏病患者的房间隔缺陷。CCN1及其同源物Ccn2(CTGF)的表达在心血管发育过程中呈重叠分布，并与血管疾病和心肌梗死密切相关。然而，Ccn2缺失的小鼠表现出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，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。这一提议试图验证这样一个假设，即CCN蛋白的不同功能背后是它们以一种上下文相关的方式调节血管生成、细胞外基质的合成或组装以及细胞生存或细胞死亡的能力。这些概念将在三个具体目标中得到检验。首先，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育中的相互作用。其次，CCN1和Ccn2可能的重叠功能将在双突变体或复合突变体中进行剖析。最后，将研究CCN蛋白在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，并阐明它们在心血管疾病中的作用。