Extracellular Proteinases in Ocular Neovascularization

描述(申请人提供)：视网膜新生血管是主要的 美国适龄劳动成年人失明的原因(糖尿病 视网膜病变)和婴儿(早产儿视网膜病变)。脉络膜 年龄相关性黄斑变性患者会发生新生血管， 60岁以上人群中最常见的致盲原因。尽管 导致视网膜和视网膜新生血管形成的确切机制 脉络膜血管生成可能是不同的，也很难理解，这是一种常见的事件 在这两种情况下都是毛细血管基底膜的破裂和 微血管内皮细胞通过血管内皮细胞的入侵和迁移 细胞外基质。血管生成的过程依赖于 丝氨酸蛋白水解酶及其受体和蛋白的表达 基质金属蛋白酶(MMPs)家族的特定成员。 了解蛋白水解酶的表达机制及鉴定 因此，它们的功能抑制物可能为 视网膜和脉络膜治疗干预的研究进展 新生血管。这个应用程序将测试视网膜和 特异性表达促进视网膜下新生血管的形成 胞外蛋白水解酶，其抑制可能导致新的和有用的 治疗。这项研究的目的是(1)解决这一假设 进一步研究胞外蛋白水解酶及其抑制物的作用 在成熟的视网膜和脉络膜新生血管模型中。我们会 使用生化、组织学和分子技术，包括使用 击倒动物，以解决这一目标。(二)确定影响因素和 调节视网膜和视网膜中蛋白水解酶表达的机制 脉络膜。研究将集中在肿瘤坏死因子α的作用上 肿瘤坏死因子α和血管生成素2在蛋白水解酶调节中的作用 单独表达或与其他生长因子和低氧联合表达 刺激。(3)确定视网膜和脉络膜的范围 可以通过使用特定的化合物来减少新生血管 直接或间接影响蛋白酶的表达和/或活性。这个 这些研究的结果将使我们能够进一步确定这些机制 参与视网膜和脉络膜中新血管的形成 导致严重的视觉并发症，以及特定阶段的 血管生成过程是治疗干预的合适靶点。是这样的 一种方法将为潜在的 眼部新生血管的有效治疗方法。

DESCRIPTION (provided by applicant): Retinal neovascularization is the leading cause of blindness in the United States among working-age adults (diabetic retinopathy) and infants (retinopathy of prematurity). Choroidal neovascularization occurs in cases of age-related macular degeneration, the most common cause of blindness in individuals over the age of 60. Although the exact mechanisms leading to the development of new vessels in retinal and choroidal angiogenesis may be different and poorly understood, a common event in both cases is the breakdown of the capillary basement membrane and the invasion and migration of microvascular endothelial cells through the extracellular matrix. The process of angiogenesis is dependent upon the expression of the serine proteinase urokinase and its receptor as well as specific members of the matrix metalloproteinase (MMP) family of enzymes. Understanding the mechanisms of proteinase expression and identifying inhibitors of their function may therefore provide unique opportunities for the development of therapeutic interventions for retinal and choroidal neovascularization. This application will test the hypothesis that retinal and subretinal neovascularization is facilitated by the expression of specific extracelluar proteinases, the inhibition of which may lead to new and useful therapies. The aims of this study which will address the hypothesis are (1) To further characterize the role of extracellular proteinases and their inhibitors in well established models of retinal and choroidal neovascularization. We will use biochemical, histological and molecular techniques, including the use of knockout animals, to address this aim. (2) To determine the factors and mechanisms which regulate the expression of proteinases in the retina and choroid. Studies will focus on the role of tumor necrosis factor alpha (TNFalpha) and angiopoietin 2 (Ang2) in the regulation of proteinase expression, alone or in combination with other growth factors and a hypoxic stimulus. (3) To determine if the extent of retinal and choroidal neovascularization can be reduced through the use of specific compounds which directly or indirectly affect proteinase expression and/or activity. The results of these studies will allow us to further define the mechanisms involved in the formation of new vessels in the retina and choroid which can lead to serious visual complications, and whether a specific stage of the angiogenic process is an appropriate target for therapeutic intervention. Such an approach will provide a rational basis for the development of potentially powerful and effective therapeutics for ocular neovascularization.