Genetics of Congenital Left-sided Heart Defects

先天性左侧心脏缺陷的遗​​传学

• 批准号: 6730642
• 负责人: Kim Lewis McBride
• 金额: $ 12.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730642
• 关键词: clinical research; congenital heart disorder; developmental genetics; echocardiography; family genetics; genetic polymorphism; genetic susceptibility; human subject; infant human (0-1 year); linkage mapping; patient oriented research; quantitative trait loci; single nucleotide polymorphism

DESCRIPTION (provided by applicant): The applicant is a clinical genetics fellow with previous broad clinical experience. The goal of this proposal is for him to become an independent clinical investigator in the genetic dissection of complex diseases, through graduate level courses and mentored research. Specific courses will include molecular genetics, genetic epidemiology, research study design, and ethical conduct of scientific research. The research setting will be the Baylor College of Medicine, a center of excellence in genetic research. Facilities include a genotyping center and a sequencing center affiliated with the Human Genome Project. Mentored research will be performed on the genetics of the left ventricular outflow tract obstruction (LVOTO) subgroup of congenital cardiovascular malformations (CCVM). This group accounts for ~20% of all CCVM and are important contributors to overall neonatal mortality. Various lines of embryological, epidemiological, and cytogenetic evidence point to the importance of genetic factors, but most cases are sporadic, indicating the genetic components are complex and do not conform to a simple pattern of inheritance. The first Specific Aim is to investigate LVOTO genetics by the linkage approach on multiplex LVOTO families and affected sib pairs. The second Specific Aim is to study family members of affected cases by echocardiography, to search for quantitative measurements that might be useful for mapping quantitative trait loci contributing to left heart development. The third Specific Aim is to establish and test affected-child/parent trios in association studies by transmission dysequilibrium and likelihood ratio analyses. Approximately 50 candidate genes, suggested primarily by mouse knockout phenotypes, will be examined in over 300 samples. The fourth Specific Aim will be to screen for mutations in candidate genes identified through animal models in the literature or identified by our linkage and association studies above. The proposed studies will launch the applicant on an independent research career, providing a base on which to advance genetic analyses of CCVM with the aim to reduce their occurrence and provide new treatment opportunities.

描述（由申请人提供）： 申请人是具有先前广泛临床经验的临床遗传学家。该提议的目的是让他通过研究生水平课程和指导的研究成为复杂疾病遗传解剖的独立临床研究者。特定的课程将包括分子遗传学，遗传流行病学，研究研究设计以及科学研究的道德行为。研究环境将是贝勒医学院，这是遗传研究卓越的中心。设施包括基因分型中心和与人类基因组项目相关的测序中心。指导的研究将对先天性心血管畸形（CCVM）的左心室流出道（LVOTO）亚组进行遗传学。该组占所有CCVM的约20％，是新生儿死亡率的重要贡献者。各种胚胎学，流行病学和细胞遗传学证据表明遗传因素的重要性，但大多数病例都是零星的，表明遗传成分很复杂，不符合简单的继承模式。第一个具体目的是通过多重LVOTO家族的链接方法研究LVOTO遗传学并影响SIB对。 第二个具体目的是通过超声心动图研究受影响病例的家庭成员，搜索可能有助于绘制有助于左心发育的定量性状基因座可能有用的定量测量值。第三个具体目的是通过传播dySequilebibrium和似然比分析在关联研究中建立和检验受影响的孩子/父型三重奏。将在300多个样本中检查大约50个候选基因，主要由小鼠敲除表型提出。第四个具体目的是筛选通过文献中的动物模型鉴定的候选基因中的突变，或通过上述联系和关联研究确定。拟议的研究将在独立的研究职业上启动申请人，为推进CCVM的遗传分析提供基础，以减少其发生并提供新的治疗机会。