DEVELOPMENT OF A TRANSGENIC MODEL OF THE MARFAN SYNDROME

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The Marfan syndrome, a heritable disorder of connective tissue with autosomal dominant transmission and a prevalence of 6-10 per 100,000 population, is a cause of severe morbidity and mortality in childhood and young adult life. Cardinal features involve the ocular, skeletal and cardiovascular systems. Biochemical studies have implicated fibrillin, the major glycoprotein component of the extracellular microfibril, in the pathogenesis of this disorder. Recent molecular genetic studies have established fibrillin gene defects as the predominant, if not the sole cause of the Marfan syndrome. In an attempt to better understand the physiology of the fibrillin protein, we propose the creation of a transgenic mouse model of the Marfan syndrome. This project will entail cloning of the 5' end of fibrillin cDNA and the 5' flanking region of the gene, identification and characterization of transcriptional control elements, in vitro analysis of the regulation of gene expression by transfection of cultured fibroblasts with mini-gene constructs, and finally, creation of transgenic mice using normal and mutant human or mouse full length fibrillin cDNA constructs. This model will allow analysis of tissue- and developmental stage-specific fibrillin expression, the role of the protein in tissue homeostasis and growth, the pathophysiology of the Marfan syndrome and other related disorders of connective tissue, and the efficacy of novel therapies which may alter the course of human disease. Curiosity regarding patterns of malformation observed during my clinical fellowship in pediatric cardiology led to a desire to explore the molecular basis of congenital and acquired heart disease. During the past 18 months, as a research fellow in the Center for Medical Genetics, I have been a central participant in the studies which established fibrillin as the defective gene in the Marfan syndrome. During this process I have learned many fundamentals of study design and molecular genetic analysis which will aid the pursuit of my long-term interests. The breadth and depth of the scientific community at the Johns Hopkins University, coupled with frequent forums for exchange of ideas, have created an ideal atmosphere for stimulation, education, and growth. In addition, I continue to benefit from the unique resources afforded by the Marfan Syndrome Clinic, the Center for Medical Genetics, and the Genetic Resources CORE Facility. I believe that my clinical training, research experience, and fortunate environment will allow me to ask and answer many questions pertinent to the normal and aberrant development of the cardiovascular system.