SCCOR in Pediatric Heart Development and Disease

描述(由申请人提供)： SCCOR将把人类患者心脏瓣膜疾病的遗传学研究与模型系统中瓣膜发育和发育不良的机制研究结合起来。该提案包括4个项目和2个核心。项目1：心脏瓣膜病的遗传学研究将使用多点方差分量连锁分析来确定与二尖瓣主动脉瓣(BAV)相关的染色体区域。在犬9号染色体上定位克隆导致犬三尖瓣畸形(类似于Ebstein畸形)的基因将直接导致对患有Ebstein异常的先证者的人类同源基因的突变分析。项目2：PTPN11突变在人类疾病中的发病机制将扩大患有和不患有Noonan综合征(NS)的心脏病患者PTPN11突变的基因-表型关系。更多的人类研究将致力于识别更多的NS基因，并确定PTPN11突变对NS患者成纤维细胞中SHP-2磷酸酶活性的影响。PTPN11突变等位基因Asn72Ser的敲入将在小鼠身上进行，作为开发NS模型的一种手段。项目3：DSCR1对瓣膜间隔发育的调控。通过激活钙调神经磷酸酶/NFAT调节DSCR1在多大程度上控制心内膜垫重塑和瓣膜间隔发育，将在三体小鼠中进行评估，并在培养的房室管外植体中进行。这些研究将为DSCR1在正常和异常瓣膜间隔发育中的作用提供遗传学和分子证据。项目4：Noonan综合征的心脏发病机制将利用对SHP-2突变的机制研究来确定导致SHP-2突变的人类心血管疾病发展的致病过程。为了实现这一目标，将利用可诱导的、基于心肌细胞和血管内皮细胞的正常和突变SHP-2表达进行全面的小鼠体内研究。行政核心(A)将作为组织的重点。表型-DNA数据库核心(B)将开发和维护一个综合的中央储存库，用于存储具有特定心脏表型的先证者的信息，这些先证者是因为他们与瓣膜心脏病的关系而被选中的。这些试剂将促进对新的候选基因和基因-表型相关性的假设检验，从而成为所有项目的宝贵资源。

DESCRIPTION (provided by applicant): The SCCOR will integrate genetic studies of valvular heart disease in human patients with mechanistic studies of valve development and maldevelopment in model systems. The proposal consists of 4 Projects and 2 Cores. Project 1: Genetic studies of valvular heart disease will use a multipoint variance-component linkage analysis to identify chromosomal regions linked to bicuspid aortic valve (BAV). Positional cloning of the gene causing canine tricuspid valve malformation (an analog of Ebstein anomaly) on canine chromosome 9 will lead directly to mutation analysis of the human homolog in probands with Ebstein anomaly. Project 2: The pathogenesis of PTPN11 mutations in human disease will expand the genotype-phenotype relations of PTPN11 mutations in cardiac patients with and without Noonan syndrome (NS). Additional human studies will be directed at identifying additional NS genes, and determining the effect of PTPN11 mutations on SHP-2 phosphatase activity in fibroblasts of NS patients. A knock-in of a PTPN11 mutant allele, Asn72Ser, will be performed in the mouse as a means to develop a model of NS. Project 3: Regulation of valvuloseptal development by DSCR1. The extent to which DSCR1 regulation by calcineurin/NFAT activation controls endocardial cushion remodeling and valvuloseptal development will be evaluated in mice trisomic for the DSCR1 locus and in cultured AV canal explants. These studies will provide genetic and molecular evidence for the role of DSCR1 in normal and abnormal valvuloseptal development. Project 4: Mechanisms of cardiac pathogenesis in Noonan syndrome will utilize mechanistic studies of SHP-2 mutations to define the pathogenic processes that underlie development of cardiovascular disease in humans with SHP-2 mutations. Comprehensive in vivo murine studies using inducible, cardiomyocyte- and endothelial-based expression of both normal and mutant SHP-2 will be utilized to achieve this goal. The Administrative Core (A) will serve as the organizational focus. The Phenotype - DNA Database Core (B) will develop and maintain an integrated central repository for information regarding probands with specific cardiac phenotypes that have been selected for their relationship to valvular heart disease. These reagents will facilitate hypothesis testing of novel candidate genes and genotype-phenotype correlations and thereby be a valuable resource for all Projects.