DEVELOPMENT OF A TRANSGENIC MODEL OF THE MARFAN SYNDROME

马凡氏综合征是一种遗传性结缔组织疾病， 常染色体显性遗传，患病率为每10万人6-10人 是儿童期发病率和死亡率高的一个原因， 年轻的成年生活。 主要特征包括眼部、骨骼和 心血管系统 生物化学研究表明， 细胞外微纤维的主要糖蛋白成分，在 这种疾病的发病机制。 最近的分子遗传学研究 建立了主要的，如果不是唯一的， 马凡氏综合征的病因 为了更好地理解这种蛋白质的生理学， 我们建议建立马凡氏综合征的转基因小鼠模型。 该项目将需要克隆的5'端的cDNA和5'端的 基因的侧翼区，鉴定和表征 转录控制元件，在体外分析的调控， 用微基因转染培养的成纤维细胞的基因表达 构建体，最后，使用正常和 突变的人或小鼠全长cDNA构建体。 该模型 将允许分析组织和发育阶段特异性的神经元， 表达，蛋白质在组织稳态和生长中的作用， 马凡氏综合征及其他相关疾病的病理生理学 结缔组织，和新的治疗，可能会改变疗效 人类疾病的过程。 关于在我的临床期间观察到的畸形模式 在儿科心脏病学的奖学金导致了探索分子的愿望， 先天性和后天性心脏病的基础。 在过去的18个月里， 作为医学遗传学中心的研究员，我一直是一个 中心参与者的研究，其中建立了作为 马凡氏综合征的缺陷基因 在这个过程中，我学到了 研究设计和分子遗传学分析的许多基本原理， 帮助我追求长远利益。 的广度和深度 约翰霍普金斯大学的科学界，加上频繁的 交流思想的论坛，创造了一个理想的气氛， 激励教育和成长 此外，我继续受益于 从马凡氏综合征诊所提供的独特资源， 医学遗传学中心和遗传资源核心设施。 我 我相信我的临床训练，研究经验，和幸运 环境将允许我提出和回答许多有关的问题 心血管系统的正常和异常发育。

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.