INTEGRINS ANGIOGENESIS AND ENDOTHELIAL CELL MIGRATION

整合素血管生成和内皮细胞迁移

• 批准号: 2459904
• 负责人: Brian P Eliceiri
• 金额: $ 2.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2459904
• 关键词: SCID mouse; angiogenesis; cell migration; enzyme activity; enzyme inhibitors; human tissue; immunofluorescence technique; integrins; isozymes; protein kinase C; tissue /cell culture; vascular endothelium; western blottings

This research proposal will focus on the biological role of protein kinase C (PKC) in alpha-v integrin-mediated endothelial cell (EC) migration and angiogenesis. Preliminary data suggests that two cytokine- dependent pathways of angiogenesis exist and are defined by their dependency on distinct vascular integrins. In vivo angiogenesis in rabbit corneal or chick chorioallantoic membrane models induced by basic fibroblast growth factor or by tumor necrosis factor alpha depended on integrin alpha-v-beta-3, whereas angiogenesis induced by phorbol esters, vascular endothelial growth factor, or transforming growth factor alpha depended on integrin alpha-v-beta-5. Monoclonal antibody antagonists to each integrin selectively blocked one of these pathways, and a cyclic pep tide antagonist of both integrins blocked angiogenesis by each cytokine tested. These pathways are further distinguished by their sensitivity to calphostin C, a PKC inhibitor, that blocked angiogenesis mediated by alpha-v-beta-5, but not alpha-v-beta-3. Therefore to examine the role of PKC in angiogenesis and EC migration, I will first identify the functionally active PKC isoforms in EC exposed to angiogenic cytokines. Second, l will identify the role of PKC in cytokine-induced integrin dependent EC motility.

这项研究计划将重点放在蛋白质的生物学作用上。 α-v整合素介导的内皮细胞中的蛋白激酶C 迁移和血管生成。初步数据显示有两种细胞因子- 血管生成的依赖途径存在，并由其定义 依赖于不同的血管整合素。兔体内血管生成的实验研究 碱性成纤维细胞生长因子诱导角膜或鸡绒毛膜尿囊膜模型 成纤维细胞生长因子或肿瘤坏死因子α依赖于 整合素α-v-β-3，而佛波酯诱导血管生成， 血管内皮生长因子，或转化生长因子α 依赖于整合素α-v-β-5。抗肿瘤单抗拮抗剂 每一种整合素都选择性地阻断了其中的一条通路，并形成了一个循环 两种整合素的潮汐拮抗剂通过各自的细胞因子阻断血管生成 测试过。这些途径的进一步区别在于它们对 Calphostin C，一种PKC抑制剂，通过以下途径阻断血管生成 阿尔法-v-β-5，但不是阿尔法-v-贝塔-3。因此，要考察 PKC在血管生成和EC迁移中的作用，我将首先确定 血管生成细胞因子作用下内皮细胞的功能活性PKC亚型。 第二，L将确定PKC在细胞因子诱导的整合素中的作用 依赖的EC运动性。