ROLE OF TIE-1 AND TIE-2 IN PATHOLOGICAL BLOOD VESSELS

TIE-1 和 TIE-2 在病理血管中的作用

• 批准号: 6450721
• 负责人: THOMAS N SATO
• 金额: $ 27.43万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450721
• 关键词: angiogenesis; animal breeding; atherosclerosis; biological signal transduction; blood vessel disorder; gene targeting; genetic promoter element; genetically modified animals; growth factor receptors; laboratory mouse; molecular pathology; protein tyrosine kinase; vascular endothelium

The long-term objectives of this project are to understand the roles of signal transduction pathways of the receptor tyrosine kinases, Tie1 and Tie2, in human pathological blood vessel formation and to develop novel therapeutics to prevent and/or cure diseases in which blood vessel formation play a role. Tie 1 and Tie2 form a novel family of vascular endothelial cell-specific receptor tyrosine kinases and they play critical roles in blood vessel formation during development. Their important functions during human pathological blood vessel growth have also been implicated. We propose the following four specific aims to accomplish our long-term goals: First, we will determine the spacial and temporal expression patterns of Tiel and Tie2 in human atherosclerotic vascular disease. Second, we will test the hypothesis that Tie1 and Tie2 have important roles in relatively mature blood vessels. This will be studied by genetically manipulating the mice so that either the Tie1 or Tie2 gene is mutated only in late embryonic stages and/or postnatal mice. Third, we will determine the roles of cytoplasmic tyrosine residues of both Tie1 and Tie2. The roles of potentially important tyrosine residues in Tie1 and Tie2 will be studied in vivo by introducing point mutations to these tyrosine residues in transgenic mice. Fourth, we will test the hypothesis that p120-GAP and p190 play critical roles in blood vessel formation in vivo. Putative dominant-negative mutant forms of p120-GAP and p190 will be over-expressed under the control of endothelial cell-specific promoters to interfere with the function of these genes, specifically in endothelial cells. These approaches will provide us with the initial step towards designing ways to manipulate the signalling pathways downstream from the Tiel and Tie2 tyrosine kinases in human vascular diseases.

该项目的长期目标是了解 受体酪氨酸激酶，TIE1和 TIE2，在人类病理血管形成并发展新颖 预防和/或治愈血管的疗法 编队起着作用。 TIE 1和TIE2形成了新型血管内皮细胞特异性家族 受体酪氨酸激酶，它们在血管中起关键作用 发展过程中的形成。它们在人类期间的重要功能 病理血管生长也已涉及。我们建议 遵循四个具体目标来实现我们的长期目标： 首先，我们将确定的时空表达模式 人类动脉粥样硬化血管疾病中的TIEL和TIE2。 其次，我们将测试TIE1和TIE2重要的假设 在相对成熟的血管中作用。这将由 遗传操纵小鼠，使TIE1或TIE2基因是 仅在胚胎晚期和/或产后小鼠中突变。 第三，我们将确定细胞质酪氨酸残基的作用 TIE1和TIE2。潜在重要重要酪氨酸残基的作用 在TIE1和TIE2中，将通过将点突变引入到体内研究 这些酪氨酸残基在转基因小鼠中。 第四，我们将测试P120存在和P190发挥关键的假设 体内血管形成中的作用。推定的显性阴性突变体 P120 GAP和P190的形式将在控制下过表达 内皮细胞特异性启动子，以干扰 这些基因，特别是在内皮细胞中。 这些方法将为我们提供设计的第一步 操纵Tiel下游的信号通路的方法 人类血管疾病中的TIE2酪氨酸激酶。