VASCULAR ENDOTHELIAL GROWTH FACTOR AND RETINAL DISEASE

描述（改编自申请人的摘要）：眼科手术 血管并发症是常见的病理反应 与涉及显著眼内缺血的病症相关。 随后视网膜的血管增生 微脉管系统常常导致不可逆的视力丧失。 这 一项研究血管内皮细胞生长的提案 血管内皮生长因子（VEGF），一种内皮细胞特异性血管生成因子， 培养的眼细胞和人眼中的血管通透性因子。 申请人已经证明了视网膜神经元上的高亲和力VEGF受体。 内皮细胞，VEGF诱导的视网膜内皮细胞增殖 细胞，缺氧诱导几种视网膜细胞VEGF mRNA的可逆性表达 类型，和VEGF升高的人眼中活跃的新血管形成。 初步数据提示VEGF受体表达与视网膜病变的发生有关。 内皮细胞受到缺氧的调节。 该提案将进一步 阐明了VEGF和VEGF受体表达与血管生成的关系， 研究缺氧对早期基因表达的影响 通过这种受体-配体相互作用诱导：（1）表征 血管内皮生长因子及其受体对实验性类脑缺血的反应 条件;（2）描绘腺苷，腺苷受体， 和抗氧化剂对缺氧诱导的VEGF及其受体表达的影响; 和（3）在人VEGF启动子中定位氧响应区 和四个分离的视网膜内皮细胞基因，其表达是 通过VEGF刺激改变。 这些调查将有助于 缺氧诱导VEGF表达的机制 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.