MOLECULAR MECHANISM OF CARDIAC OUTFLOW TRACT DEVELOPMENT

心脏流出道发育的分子机制

• 批准号: 6856517
• 负责人: SULAGNA C SAITTA
• 金额: $ 13.02万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856517
• 关键词: DNA binding protein; DiGeorge' s syndrome; chemical structure function; chromosome deletion; clinical research; congenital cardiovascular disorder; embryo /fetus cell /tissue; endothelin; functional /structural genomics; gender difference; gene expression; genetic mapping; genetic recombination; histogenesis; hormone receptor; human genetic material tag; human population genetics; human subject; in situ hybridization; intermolecular interaction; laboratory mouse; meiosis; molecular cloning; molecular genetics; nucleic acid structure; polymerase chain reaction; velocardiofacial syndrome

(Adapted from applicant?s abstract) The process of cardiac development is extraordinarily complex requiring precise coordination of gene expression. Conotruncal development is an essential step in cardiogenesis, and disturbances in this process can result in severe life-threatening congenital cardiac defects. Such malformations are present in 85 percent of patients with velocardiofacial/DiGeorge syndrome (VCFS) and are the major cause of morbidity and mortality in these patients. Detectable deletions of chromosome 22q11.2 are found in approximately 90 percent of these patients and are estimated to occur at an extremely high frequency in the general population (1/3,000-4,000 live births), making them a significant health concern. The molecular mechanisms by which the deletion occurs is largely unknown. This proposal seeks to examine the genetic mechanisms of the most frequent human microdeletion syndrome. Recent data from our laboratory and others have shown the existence of large low copy repeats in the 22q11 deletion interval. We hypothesize that the location of the low copy repeats near the deletion endpoints(DEPs) plays a significant role in the mechanism of deletion formation. Using our extensive patient cohort for haplotype reconstruction, we will analyze sequences flanking the repeats and trace de novo deleted alleles in parental and granparental meioses. We will also determine whether inter- or intra- chromosomal events predominate and if the sex of the parent of origin affects the mechanism of deletion formation. Additionally, we have recently described a novel 22q11.2 deletion, in a patient with outflow tract defects and VCFS. This patient is deleted for a different set of genes than those thought to result in the conotruncal phenotype associated with VCFS. Using this unique resource we will identify and examine the genes present in the novel deletion interval, and assess their potential contribution to conotruncal development. Here we describe a five-year training program in which the applicant will acquire the skills and experience required of an independent physician scientist. The primary focus throughout the grant period, will be to provide broad and in-depth training in the areas of genomic structure and instability which lead to human disease, and genetic mechanisms involved in the developmental patterning of the heart. These studies will utilize the expertise of the mentors, and will enable the candidate to transition into an investigator capable of directing future studies of the molecular basis of development and human genetic disease. (End of Abstract)

（改编自申请人的摘要）心脏发育的过程是 异常复杂，需要基因表达的精确协调。 圆锥干发育是心脏发生的重要步骤，并且 这一过程的紊乱可能会导致严重危及生命的先天性疾病 心脏缺陷。 85%的患者存在此类畸形 患有腭心面/迪乔治综合征 (VCFS)，是导致 这些患者的发病率和死亡率。可检测到的染色体缺失 22q11.2 存在于大约 90% 的患者中，并且 估计在一般人群中发生的频率极高 （1/3,000-4,000 活产），使它们成为一个重大的健康问题。这 发生缺失的分子机制很大程度上是未知的。这 该提案旨在研究最常见的人类遗传机制 微缺失综合征。我们实验室和其他实验室的最新数据表明 22q11 缺失区间存在大量低拷贝重复序列。我们 假设低拷贝的位置在删除附近重复 端点（DEP）在删除机制中起着重要作用 形成。使用我们广泛的患者队列进行单倍型重建， 我们将分析重复序列侧翼的序列并追踪从头删除 亲本和祖父母减数分裂中的等位基因。我们还将确定是否 染色体间或染色体内事件占主导地位，并且如果父母的性别 起源影响缺失形成的机制。此外，我们还有 最近描述了一名患有流出道的患者的一种新的 22q11.2 缺失 缺陷和 VCFS。该患者因一组不同的基因而被删除 这些被认为会导致与 VCFS 相关的圆锥干表型。 利用这种独特的资源，我们将识别和检查存在于 新的删除间隔，并评估它们对 躯干发育。 在这里，我们描述了一个为期五年的培训计划，申请人将在其中 获得独立医生所需的技能和经验 科学家。整个拨款期间的主要重点将是提供 基因组结构和不稳定性领域的广泛而深入的培训 导致人类疾病的遗传机制 心脏的发育模式。这些研究将利用 导师的专业知识，将使候选人能够过渡到 能够指导未来分子基础研究的研究者 发育与人类遗传疾病。 （摘要完）