Integrin-Matrix Interaction in Cardiovascular Development

心血管发育中的整合素-基质相互作用

基本信息

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
项目类别：
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

项目摘要

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，并且非常容易受到遗传扰动的影响。最近的研究发现转录因子网络在调节心血管发育中发挥着关键作用。然而，对于细胞外基质信号如何控制细胞行为，人们知之甚少。最近已经确定了 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。 Ccn1缺失小鼠由于血管分叉、血管完整性和房室瓣膜形态发生受损而遭受胚胎死亡。尽管 Ccn1 小鼠基本上可以存活，但其中 20% 表现出房间隔缺损，类似于一些人类先天性心脏病患者的房间隔缺损。 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，并与血管疾病和心肌梗塞密切相关。然而，Ccn2 缺失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。从机制上讲，CCN 蛋白直接与不同的整合素结合，这些整合素已被证明可以介导细胞培养系统中的各种 CCN 活性。然而，整合素在 CCN 蛋白体内功能中的作用尚不清楚。该提案旨在检验以下假设：CCN 蛋白的多种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，确定CCN1在维持血管结构中的作用，以及CCN1-a的贡献？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。