SCCOR in Pediatric Heart Development and Disease

SCCOR 在小儿心脏发育和疾病中的应用

• 批准号: 6698710
• 负责人: Dudley Woodrow (Woody) Benson
• 金额: $ 253.22万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698710
• 关键词: cardiogenesis; clinical research; congenital heart disorder; human subject; pediatrics

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.

描述（由申请人提供）： SCCOR 将把人类患者瓣膜性心脏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。该提案由 4 个项目和 2 个核心组成。项目 1：瓣膜性心脏病的遗传学研究将使用多点方差分量连锁分析来识别与二叶式主动脉瓣 (BAV) 相关的染色体区域。在犬第 9 号染色体上对导致犬三尖瓣畸形（Ebstein 异常的类似物）的基因进行定位克隆，将直接导致对 Ebstein 异常先证者中的人类同源物进行突变分析。项目2：人类疾病中PTPN11突变的发病机制将扩大患有和不患有努南综合征（NS）的心脏病患者中PTPN11突变的基因型-表型关系。其他人体研究将旨在识别其他 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。将在小鼠中敲入 PTPN11 突变等位基因 Asn72Ser，作为开发 NS 模型的手段。项目 3：DSCR1 调节瓣膜间隔发育。钙调神经磷酸酶/NFAT 激活对 DSCR1 的调节控制心内膜垫重塑和瓣膜间隔发育的程度将在 DSCR1 基因座三体小鼠和培养的 AV 管外植体中进行评估。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和分子证据。项目 4：Noonan 综合征的心脏发病机制将利用 SHP-2 突变的机制研究来定义 SHP-2 突变人类心血管疾病发展的致病过程。将利用正常和突变 SHP-2 的诱导型、基于心肌细胞和内皮的表达的全面的小鼠体内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) 将开发和维护一个集成的中央存储库，用于存储具有特定心脏表型的先证者的信息，这些表型是因其与瓣膜性心脏病的关系而被选择的。这些试剂将促进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。