GENES FOR VASCULAR MORPHOGENESIS: A GENETIC APPROACH

我们研究的长期目标是发现 参与心血管系统发育的机制。 我们使用人类遗传学方法作为了解遗传过程的窗口 参与心脏和血管的发育。我们目前正在 用这种方法来鉴定Klippel-Trenaunay综合征的第一个基因 (KTS)，这是一种血管疾病，包括毛细血管，淋巴管， 与骨和软组织肥大相关的静脉畸形。因为 KTS是一种血管异常，我们认为KTS的发病机制涉及血管内皮细胞， 胚胎期血管形态发生关键基因的破坏 发展我们的特点是KTS易位涉及5号染色体 和11，并鉴定了一种新的血管基因，VEG 5 Q（血管内皮基因 5 q上），为KTS的强候选基因。本提案的目标是 利用这些独特的资源来功能性地表征VEG 5 Q基因， 研究其在血管形态发生中的正常功能， 阐明KTS相关突变的致病机制。具体 目的：1）VEGF 5 Q的分子特征，一个新的血管基因， KTS的有力候选人。2)为了产生小鼠模型， VEGF 5 Q在血管形态发生中的作用。3)来鉴定那些与 关于VEG 5 Q 4)KTS患者的基因型-表型相关性研究， 与11 p易位相关基因的鉴定/表征 断点。5)鉴定差异表达的基因， KTS患者使用基因芯片技术。 本研究目标的成功实现应使我们能够 了解KTS的分子机制以及其他常见的 血管疾病，如静脉曲张和静脉畸形。的 KTS基因的可用性提供了基础，并提供了令人兴奋的 表征血管基础分子机制的可能性 形态发生此外，了解KTS的遗传机制 为治疗KTS以及癌症等疾病提供了可能性， 依赖于血管生成。

The long-term objective of our research is to discover the molecular mechanisms involved in the development of the cardiovascular system. We use the human genetic approach as the window into the genetic processes involved in the development of the heart and blood vessels. We are currently using this approach to identify the first gene for Klippel-Trenaunay syndrome (KTS), which is a vascular disease comprised of capillary, lymphatic, and venous malformations associated with bony and soft tissue hypertrophy. Because KTS is a vascular anomaly, we propose that KTS pathogenesis involves the disruption of the key genes for vascular morphogenesis during embryonic development. We have characterized a KTS translocation involving chromosomes 5 and 11, and identified a novel vascular gene, VEG5Q (Vascular Endothelial Gene on 5q), as the strong candidate gene for KTS. The goals of this proposal are to use these unique resources to functionally characterize the VEG5Q gene, to investigate its normal function involved in vascular morphogenesis, and to elucidate the pathogenic mechanisms of KTS-associated mutations. The specific aims are: 1) Molecular characterization of VEG5Q, a novel vascular gene and a strong candidate for KTS. 2) To generate mouse models that will elucidate the role of VEG5Q in vascular morphogenesis. 3) To identify proteins that interact with VEG5Q. 4) Genotype-phenotype correlation studies of KTS patients and identification/characterization of genes associated with 11p translocation breakpoint. 5) Identification of genes which are differentially expressed in KTS patients using the Gene-Chip technology. The successful accomplishment of goals in this study should allow us to understand the molecular mechanisms underlying KTS as well as other common vascular disorders such as varicose veins and venous malformations. The availability of KTS genes provides the groundwork and offers the exciting possibility of characterizing the molecular mechanisms underlying vascular morphogenesis. Moreover, understanding the genetic mechanisms underlying KTS offers possibilities for treatment of KTS as well as conditions such as cancer that depend on angiogenesis.