DEVELOPMENT OF A TRANSGENIC MODEL OF THE MARFAN SYNDROME

马凡综合征是一种遗传性结缔组织疾病， 常染色体显性遗传和每10万人中有6-10人流行 人口，是儿童严重发病和死亡的原因 年轻的成年人的生活。主要特征包括眼部、骨骼和 心血管系统。生化研究表明，纤维蛋白是 细胞外微原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已经 确定纤维蛋白基因缺陷是主要的，如果不是唯一的 马凡综合症的起因。 为了更好地了解纤维蛋白的生理学， 我们建议建立一个马凡综合征的转基因小鼠模型。 该项目将需要克隆原纤维蛋白基因的5‘端和5’端 基因侧翼区的克隆、鉴定和鉴定 转录调控元件的体外调控分析 微基因导入培养成纤维细胞的基因表达 构建，最后，使用正常和 突变的人或鼠的全长纤维蛋白基因的构建。这款车 将能够分析特定组织和发育阶段的纤维蛋白 表达，蛋白质在组织动态平衡和生长中的作用 马凡综合征及其他相关疾病的病理生理学研究 结缔组织，以及新疗法的疗效，可能改变 人类疾病的进程。 对我在临床上观察到的畸形模式的好奇心 儿科心脏病学方面的研究使人们渴望探索分子 先天性和获得性心脏病的基础。在过去18个月里， 作为医学遗传学中心的一名研究员，我一直是 研究的中心参与者，这些研究将纤维蛋白确立为 马凡综合征的基因缺陷。在这个过程中，我学到了 研究设计和分子遗传分析的许多基础知识将 帮助我追求长远利益。它的广度和深度 约翰·霍普金斯大学的科学界，加上频繁的 交流思想的论坛，创造了理想的氛围 刺激、教育和成长。此外，我继续受益于 从马凡综合症诊所提供的独特资源中， 医学遗传学中心和遗传资源核心设施。我 相信我的临床培训、研究经验和幸运 环境将允许我提出和回答许多与 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.