The Genetic Etiology of Patent Ductus Arteriosus

描述（由申请人编写）：血管重塑 对各种刺激作出反应的血管结构是各种血管结构的基础， 流程.阐明这些过程的分子基础可能具有 对心血管疾病的理解和治疗的重要意义 疾病这些疾病的确切病理生理机制仍然存在 未知，主要是因为它们只能在完整的背景下进行研究。 生理系统以复杂的方式相互作用的生物体。 血管重塑的一个显著例子是导管的快速闭合 出生后的动脉。 出生后闭合失败， 动脉导管未闭（PDA）是生殖道最常见的并发症之一， 心血管缺陷了解专利的分子基础 因此，动脉导管（PDA）揭示了动脉导管的基本过程。 各种血管疾病。我们已经定位了两个常染色体隐性基因 染色体12 q24和5 p13上的PDA，具有显著LOD评分5.32和5.4 在染色体5 q23 -24上有一个显性PDA基因， LOD评分为3.5。我们设想通过定位克隆来鉴定这些基因。 随后的步骤将包括疾病基因产物的定位， 正常和疾病组织以及基因敲除小鼠的发育。我们预计 PDA基因鉴定及其定位和功能研究 可以提供对不同形式的血管的基础过程的关键见解， 重塑，并将提高对血管生物学的理解。 我的职业目标是研究血管重塑的病理生理学 从PDA的遗传原因开始。指导临床科学家 发展奖将提供必要的分子遗传学培训， 实现这些目标。利夫顿博士是心血管领域公认的领导者 遗传学和他的指导是我职业发展的重要组成部分。的 耶鲁大学的内科和遗传学系拥有广泛的资源 利夫顿博士的实验室为获得 我的研究生涯所需要的调查技能该奖项提供 发展职业生涯的重要组成部分，并将最大限度地提高我的学术 潜力

DESCRIPTION (prepared by applicant): The remodeling of blood vessel architecture in response to various stimuli underlies a wide range of vascular processes. Elucidation of the molecular basis of these processes may have important implications for the understanding and treatment of cardiovascular disease. The exact pathophysiologic mechanisms of these disorders remain unknown, largely because they can be studied only in the context of intact living organisms where physiologic systems interact in a complex fashion. One dramatic example of vascular remodeling is the rapid closure of the ductus arteriosus following birth. Failure of postnatal closure of this muscular artery, patent ductus arteriosus (PDA), is one of the most common genital cardiovascular defects. Understanding of the molecular basis of the patent ductus arteriosus (PDA) lay therefore shed light on fundamental processes of a variety of vascular disorders. We have mapped two genes autosomal recessive PDA on chromosomes 12q24 and 5p13 with significant LOD scores of 5.32 and 5.4 respectively, and one gene for dominant PDA on chromosome 5q23-24 with maximum LOD Score of 3.5. We envision identifying these genes by positional cloning. Subsequent steps will include localization of the disease gene products in normal and disease tissue and development of knock out mice. We expect that identification PDA genes and understanding of their localization and function may provide key insights into processes underlying different forms of vascular remodeling and will enhance understanding of vascular biology. My career goals are to investigate the pathophysiology of vascular remodeling beginning with the genetic causes of PDA. The Mentored Clinical Scientist Development Award will provide the necessary training in molecular genetics to accomplish these goals. Dr. Lifton is a recognized leader in cardiovascular genetics and his mentorship is a vital component to my career development. The Departments of Internal Medicine and Genetic Yale with the extensive resources of the Dr. Lifton' s laboratory provide an ideal environment for acquiring the vestigative skills needed to launch my research career. This award provides the essential components to develop career and will maximize my academic potential.