SCCOR in Pediatric Heart Development and Disease

描述（由申请人提供）： SCCOR将整合人类患者心脏瓣膜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。该项目包括4个项目和2个核心。项目一：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叶式主动脉瓣（BAV）相关的染色体区域。在犬9号染色体上定位克隆引起犬三尖瓣畸形（Ebstein异常的类似物）的基因将直接导致Ebstein异常先证者中人类同源物的突变分析。项目二：PTPN 11突变在人类疾病中的发病机制将扩大PTPN 11突变在努南综合征（NS）和非努南综合征（NS）心脏病患者中的基因型-表型关系。另外的人体研究将针对鉴定另外的NS基因，并确定PTPN 11突变对NS患者成纤维细胞中SHP-2磷酸酶活性的影响。将在小鼠中进行PTPN 11突变等位基因Asn 72 Ser的敲入，作为开发NS模型的方法。项目3：DSCR 1对瓣膜间隔发育的调节。通过钙调磷酸酶/NFAT激活的DSCR 1调节控制内膜垫重塑和瓣膜间隔发育的程度将在DSCR 1基因座的小鼠三体和培养的AV管外植体中进行评价。这些研究将为DSCR 1在正常和异常瓣膜间隔发育中的作用提供遗传和分子证据。项目四：努南综合征的心脏发病机制将利用SHP-2突变的机制研究来确定SHP-2突变人群心血管疾病发展的致病过程。将利用利用正常和突变SHP-2两者的基于诱导型、心肌细胞和内皮细胞的表达的全面体内小鼠研究来实现这一目标。行政核心（A）将作为组织重点。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，用于收集关于具有特定心脏表型的先证者的信息，这些表型是根据其与心脏瓣膜病的关系而选择的。这些试剂将有助于新候选基因和基因型-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.