The Genetic Etiology of Patent Ductus Arteriosus

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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.