The Genetic Etiology of Patent Ductus Arteriosus

描述(申请人编写)：血管重塑 对各种刺激作出反应的建筑构成了多种血管的基础 流程。对这些过程的分子基础的阐明可能有 对心血管疾病的认识和治疗的重要意义 疾病。这些疾病的确切病理生理机制仍然存在。 未知，很大程度上是因为它们只能在完整的背景下进行研究 生物体，其中生理系统以复杂的方式相互作用。 血管重塑的一个戏剧性例子是导管迅速闭合。 出生后出现动脉硬化。这块肌肉的出生后闭合失败 动脉导管未闭(PDA)是最常见的生殖器之一 心血管缺陷。对专利的分子基础的理解 因此，动脉导管(PDA)的铺设揭示了 各种血管疾病。我们已经定位了两个常染色体隐性遗传基因 位于染色体12q24和5p13上的PDA，显著LOD分数分别为5.32和5.4 分别位于染色体5q23-24上的1个显性PDA基因 LOD得分为3.5。我们设想通过位置克隆来识别这些基因。 后续步骤将包括疾病基因产品的本地化 正常和疾病组织及基因敲除小鼠的发育。我们期待着 PDA基因的鉴定及其定位和功能的理解 可以为不同形式的血管的潜在过程提供关键的见解 重塑，并将加强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。被指导的临床科学家 发展奖将提供必要的分子遗传学培训，以 完成这些目标。利夫顿博士是公认的心血管领域的领导者 遗传学和他的指导对我的职业发展至关重要。这个 拥有广泛资源的耶鲁大学内科和遗传学系 利夫顿博士的S实验室为获得 开始我的研究事业所需要的调查技能。该奖项提供了 发展事业的基本要素，并将使我的学业最大化 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.