SCOR IN PEDIATRIC CARDIOVASCULAR DISEASE

小儿心血管疾病中的 SCOR

• 批准号: 2228365
• 负责人: CLAYTON A BUCK
• 金额: $ 116.64万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2228365
• 关键词: congenital heart disorder; developmental genetics

Eight out of every thousands infants in the United States are born with a congenital heart defect. The most common involve the conotruncus or outflow tract of the heart. Little is known concerning the etiology of these abnormalities. The purpose of this SCOR is to identify and characterize genes required for early conotruncal morphogenesis. The approach is based upon our observation that patients suffering from DiGeorge Syndrome (DGS), Velo-Cardio-Facial syndrome (VCFS) and 30% of children with congenital abnormalities of the outflow tract of the heart (excluding those with DGS and VCFS) all carry microdeletions within chromosomal region 22q11. The fact that all tissues affected in these patients are dependent upon the cranial neural crest during early development, along with the shared genetic abnormality suggest a common etiology of these congenital defects. Further, they suggest that within chromosome 22q11 lie a gene or set of genes programmed for expression during this critical period of heart morphogenesis. Guided by these observations, we have organized 4 projects and 4 cores with the goal of isolating and characterizing genes required for conotruncal development. Our program will utilize three model systems, the human newborn with nonsyndromic conotruncal defects, the mouse embryo and mouse strains presenting conotruncal defects, and the chick embryo. Project 1, the clinical project, provides the focus for the other three projects. Project 1, with the support of the Clinical Core (A) and the Cell and Molecular Biology Core (B) will identify and evaluate newborns with conotruncal heart defects to delineate the region of chromosome 22q11 deleted. Genes within this region will be isolated, sequenced and mapped within 22q11 by Project 2 with the support of Core B and the DNA Sequencing and Analysis Core (C). Project 3 will evaluate the role of these candidate genes in mouse development as well as provide cDNA unique to cardiac neural crest for molecular evaluation in project 2 and genetic evaluation in project 1. This project will utilize both normal and trisomy mouse embryos (all of which have conotruncal defects) to evaluate neural crest function and identify possible candidate genes for analysis within the other 3 projects. The evaluation of neural crest behavior will be in collaboration with project 4. Project 4 provides the experimental embryology required for detailed evaluation of the candidate genes in cardiac neural crest function using the avian embryo in which cardiac neural crest behavior and function is best described. Upon completion of the work proposed here, we will have identified and mapped genes critical to early heart development within human chromosome 22q11 as well as identified and characterized other genes critical to outflow tract morphogenesis.

在美国，每千名婴儿中就有八名 先天性心脏病 最常见的涉及圆锥干或 心脏流出道 关于其病因学知之甚少。 这些异常。 本SCOR的目的是确定和 鉴定早期圆锥干形态发生所需的基因。 的 这种方法是基于我们的观察， DiGeorge综合征（DGS），Velo-Cardio-Facial综合征（VCFS）和30%的 先天性心脏流出道畸形儿童 （不包括DGS和VCFS）都携带微缺失， 染色体区域22 q11。 事实上，所有受影响的组织在这些 患者在早期依赖于颅神经嵴， 发育，沿着共同的遗传异常表明， 这些先天性缺陷的病因。 此外，他们认为，在 染色体22 q11是一个基因或一组基因的表达程序 心脏形态发生的关键时期 时遵循这些 我们组织了4个项目和4个核心，目标是 分离和鉴定圆锥体干发育所需的基因。 我们的计划将利用三个模型系统，人类新生儿与 非综合征性圆锥动脉干缺陷，小鼠胚胎和小鼠品系 出现圆锥动脉干缺陷和鸡胚。 项目1， 临床项目，为其他三个项目提供了重点。 项目1，在临床核心（A）和Cell的支持下， 分子生物学核心（B）将识别和评估新生儿， 圆锥动脉干心脏缺陷，以描绘染色体22 q11区域 的页面不存在或 这个区域内的基因将被分离、测序和绘制地图 在核心B和DNA的支持下， 测序和分析核心（C）。 项目3将评估以下方面的作用： 这些候选基因在小鼠发育中的作用， 心脏神经嵴的分子评价项目2和遗传 项目评价1。 该项目将利用正常和 三体性小鼠胚胎（均具有圆锥动脉干缺陷）进行评估 神经嵴功能，并确定可能的候选基因进行分析 在其他三个项目中。 神经嵴行为的评价 将与项目4合作。 项目4提供了 详细评估候选人所需的实验胚胎学 心脏神经嵴功能的基因， 心脏神经嵴的行为和功能得到了最好的描述。 后 完成这里提出的工作，我们将确定和绘制 人类染色体22 q11中对早期心脏发育至关重要的基因 以及其他对流出至关重要的基因 束形态发生