VASCULAR ENDOTHELIAL GROWTH FACTOR AND RETINAL DISEASE

描述(摘自申请者的摘要)：增生性眼球 血管并发症是一种常见的病理反应 与严重的眼内缺血相关的疾病。 随后视网膜的旺盛血管增殖 微血管系统常常导致不可逆转的视力丧失。这 研究血管内皮细胞生长的作用的提案 血管内皮生长因子(VEGF)，一种内皮细胞特异性的血管生成和 培养的眼细胞和人眼的血管通透性因子。 申请人已证明视网膜上有高亲和力的血管内皮生长因子受体 血管内皮细胞，血管内皮生长因子诱导的视网膜内皮细胞增殖 缺氧诱导几种视网膜细胞可逆的血管内皮生长因子基因表达 新生血管活跃的人眼的类型和血管内皮生长因子的升高。 初步数据提示血管内皮生长因子受体的表达与视网膜 血管内皮细胞受低氧调节。这项提议将进一步 阐明血管内皮生长因子及其受体表达的机制 并研究早期基因表达的变化 由这种受体-配体相互作用引起的：(1)表征 血管内皮生长因子及其受体对实验性缺血样反应的影响 条件；(2)描绘腺苷、腺苷受体、 以及抗氧化剂对低氧诱导的血管内皮生长因子及其受体表达的影响； 以及(3)定位人血管内皮生长因子启动子中的氧响应区 和四个分离的视网膜内皮细胞基因，它们的表达是 受血管内皮细胞生长因子刺激改变。这些调查将有助于描述 低氧诱导血管内皮细胞生长因子表达的作用机制 发生。

DESCRIPTION (Adapted from applicant's abstract): Proliferative ocular vascular complications constitute a common pathological response associated with disorders involving significant intraocular ischemia. The subsequent exuberant vasoproliferation of the retinal microvasculature often results in irreversible vision loss. This proposal investigates the role of vascular endothelial cell growth factor (VEGF), an endothelial cell-specific angiogenic and vasopermeability factor in cultured ocular cells and in the human eye. The applicant has demonstrated high affinity VEGF receptors on retinal endothelial cells, VEGF-induced proliferation of retinal endothelial cells, reversible VEGF mRNA induction by hypoxia in several retinal cell types, and VEGF elevation in human eyes with active neovascularization. Preliminary data suggested VEGF receptor expression and retinal endothelial cells was modulated by hypoxia. This proposal will further delineate the mechanism by which VEGF and VEGF receptor expression are modulated by hypoxia and investigate the early gene expression changes induced by this receptor-ligand interaction by: (1) characterizing the response of VEGF and VEGF receptor to experimental ischemia-like conditions; (2) delineating the role of adenosine, adenosine receptors, and antioxidants on hypoxia-induced VEGF and VEGF receptor expression; and (3) locating oxygen-responsive regions in the human VEGF promoter and four isolated retinal endothelial cell genes whose expression is altered by VEGF stimulation. These investigations will help delineate the mechanisms by which hypoxia-induced VEGF expression in VEGF action occur.