Extracellular Proteinases in Ocular Neovascularization

描述（由申请人提供）：视网膜新生血管是主要的 美国工作年龄成年人的致盲原因（糖尿病 视网膜病）和婴儿（早产儿视网膜病）。脉络膜 新血管形成发生在年龄相关性黄斑变性的情况下， 这是60岁以上人群失明的最常见原因。虽然 导致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，了解不多，一个共同的事件， 在这两种情况下，都是毛细血管基底膜的破裂， 微血管内皮细胞的侵袭和迁移 细胞外基质血管生成的过程依赖于 丝氨酸蛋白酶尿激酶及其受体的表达， 基质金属蛋白酶（MMP）家族酶的特定成员。 了解蛋白酶的表达机制， 因此，其功能的抑制剂可能为这些疾病提供独特的机会。 视网膜和脉络膜的治疗干预的发展 新生血管形成这个应用程序将测试假设，视网膜和 视网膜下新生血管化是通过表达特异性 细胞外蛋白酶，其抑制可能导致新的和有用的 治疗本研究的目的是解决这一假设：（1） 进一步表征细胞外蛋白酶及其抑制剂的作用， 在视网膜和脉络膜新生血管的良好建立的模型中。我们将 使用生物化学、组织学和分子技术，包括使用 淘汰动物，以实现这一目标。(2)为了确定这些因素， 调节视网膜中蛋白酶表达的机制， 脉络膜研究将集中在肿瘤坏死因子α的作用 （TNF α）和血管生成素2（Ang 2）在调节蛋白酶 表达，单独或与其他生长因子和低氧 刺激。(3)为了确定视网膜和脉络膜的程度 通过使用特定的化合物可以减少新血管形成，所述化合物 直接或间接影响蛋白酶的表达和/或活性。的 这些研究的结果将使我们能够进一步确定机制， 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，以及是否在特定阶段的 血管生成过程是治疗干预的适当靶点。等 一种方法将为潜在的发展提供合理的基础， 是治疗眼部新生血管形成的有效药物。

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.