Molecular basis for vascular malformations

血管畸形的分子基础

• 批准号: 6878002
• 负责人: DEAN Yaw LI
• 金额: $ 10.77万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878002
• 关键词: angiogenesis; ankyrins; blood vessel disorder; congenital cardiovascular disorder; developmental genetics; gene targeting; growth factor receptors; laboratory mouse; molecular pathology; protein kinase; protein protein interaction; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): KRIT-1 is an intracellular protein that interacts with the RAS family of GTPases. Recently loss-of-function mutations in KRIT-1 were found to be responsible for an autosomal dominant human vascular dysplasia, cerebral cavaernous malformations (CCM). My laboratory independently cloned the KRIT-1 gene in a screen for genes differentially expressed in mice lacking activin receptor-like kinase 1, Alk-1. Los of function mutations is A1k1 is responsible for another autosomal dominant vascular dysplasia, hereditary hemorrhagic telangiectasia (HM I). In both CCM and HHT, there are abnormal dilated sacs of endothelium that cause morbidity by hemorrhaging or expanding. Our previous studies demonstrated that Alk-1 regulates endothelial cell (EC) maturation and establishes arterial identity. Our identification of KRIT-I as a differentially expressed gene in Alk1 4- mice, and the involvement of both genes in the etiology of vascular dysplasias suggest that KRIT-1 mediates endothelial cell maturation and is essential for angiogenesis, we propose three specific aims. (1) Determine whether KRIT-1 is essential for vessel development by generating and characterizing gene targeted mice, (2) Examine whether KRIT-I mediates EC maturation using an in vitro cell culture system. (3) Identify novel molecular events that are downstream of KRIT-1, expressed in the endothelium, and essential for vessel development. This grant application seeks to describe a role for KRIT-1 in vascular development and define a molecular pathway for endothelial maturation. We postulate that many vascular dysplasias are the result of genetic defects along a common molecular pathway that regulates endothelial maturation. Dr. Li is an independent scientist who has made significant contributions to the study of vascular development. The NHLBI K02 Independent Scientist Award will enable him to concentrate over 90 percent of his time on research by horning his clinical, administrative and teaching responsibilities. With this time, Dr. Li will develop a new project that will enhance our fundamental understanding of vascular development and discase.

描述（由申请人提供）： KRIT-1 是一种细胞内蛋白，与 RAS 家族相互作用 GT酶。 最近发现 KRIT-1 的功能丧失突变 负责常染色体显性人类血管发育不良，脑 海绵状血管畸形（CCM）。 我实验室自主克隆KRIT-1 筛选缺乏激活素的小鼠中差异表达的基因 受体样激酶 1，Alk-1。 功能丧失突变是 A1k1 是 导致另一种常染色体显性血管发育不良，遗传性 出血性毛细血管扩张症（HM I）。 CCM和HHT均存在异常 扩张的内皮囊，因出血或扩张而导致发病。 我们之前的研究表明Alk-1可以调节内皮细胞（EC） 成熟并建立动脉特性。 我们对 KRIT-I 的鉴定为 Alk1 4-小鼠中差异表达的基因，以及两者的参与 血管发育不良病因中的基因表明 KRIT-1 介导 内皮细胞成熟并且对于血管生成至关重要，我们建议 三个具体目标。 (1) 确定KRIT-1对于船舶是否是必需的 通过生成和表征基因靶向小鼠来进行发育，（2）检查 KRIT-I 是否使用体外细胞培养系统介导 EC 成熟。 (3) 识别 KRIT-1 下游的新分子事件，表达 在内皮细胞中，对于血管发育至关重要。 这笔补助金 该申请旨在描述 KRIT-1 在血管发育和 定义内皮成熟的分子途径。 我们假设有很多 血管发育不良是沿共同分子遗传缺陷的结果 调节内皮成熟的途径。 李博士是一位独立科学家，为人类健康事业做出了重大贡献 血管发育的研究。 NHLBI K02 独立 科学家奖将使他能够将 90% 以上的时间集中在 通过提高临床、行政和教学水平进行研究 责任。 利用这段时间，李博士将开发一个新项目， 增强我们对血管发育和疾病的基本了解。