SCOR IN PEDIATRIC CARDIOVASCULAR DISEASE

在美国，每千名婴儿中就有八名出生时患有 先天性心脏病。最常见的是圆锥主干或 心脏流出道。目前对该病的病因知之甚少 这些反常现象。本SCOR的目的是识别和 鉴定早期锥体干形态发生所需的基因。这个 方法是基于我们的观察，患者患有 DiGeorge综合征(DGS)、血管-心脏-面部综合征(VCFS)和30% 先天性心脏流出道异常的儿童 (不包括那些带有DGS和VCFS的)都带有微缺失 染色体22q11区。事实上，所有受影响的组织 患者在早期依赖于颅神经脊 发育，以及共同的基因异常表明 这些先天缺陷的病因。此外，他们还表示，在 染色体22q11是为表达而编程的一个或一组基因 在心脏形态发生的关键时期。在这些指导下 观察，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，人类新生儿和 非综合征圆锥干畸形、小鼠胚胎和小鼠品系 表现为圆锥干缺陷和鸡胚。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)和细胞和 分子生物学核心(B)将识别和评估患有 圆锥干心脏缺陷区22q11区域的定位 已删除。该区域内的基因将被分离、测序和绘制图谱 在核心B和DNA的支持下，项目2在22Q11内完成 测序和分析核心(C)。项目3将评估 这些候选基因在小鼠的发育过程中以及提供了独特的cDNAs 在项目2和遗传学中对心脏神经脊进行分子评估 项目1中的评估。该项目将使用常规和 评估小鼠三体胚胎(所有胚胎都有圆锥干缺陷) 神经脊功能和识别可能的候选基因进行分析 在其他3个项目中。神经脊线行为的评价 将与项目4合作。项目4提供 详细评估候选人所需的实验胚胎学 利用禽类胚胎的心脏神经脊功能的基因 心脏神经脊的行为和功能是最好的描述。vt.在.的基础上 在完成这里提出的工作后，我们将确定并绘制 人类染色体22q11中对心脏早期发育至关重要的基因 以及识别和表征其他对外流至关重要的基因 束形态发生。

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.