Thrombospondin-1 and retininal vascular homeostasis

描述（由申请人提供）：糖尿病主要影响视网膜的微血管循环，导致该组织特有的一系列结构变化。 这些变化包括视网膜微血管周细胞的早期持续损失、基底膜增厚，随后是内皮细胞（EC）的过度增殖和视网膜的异常血管化，其最终导致失明。 视网膜血管化通常限于视网膜的表层和深层。 其他眼部部位，如角膜、透镜和玻璃体，通常无血管。 据推测，负调节血管生成是负责这些血管的限制。 我们最近已经证明，血小板反应蛋白-1（TSP 1），一种有效的天然血管生成抑制剂，存在于眼部无血管部位，并且TSPt表达在糖尿病中显著下调。 我们的假设是，TSP 1是视网膜血管稳态的重要调节剂，其在病理条件如糖尿病和/或缺血下的改变导致视网膜新生血管形成。 本研究将探讨TSP 1在视网膜血管发育和缺血诱导的新生血管形成中的作用。 我们将研究TSP 1在视网膜和视网膜毛细血管发育过程中的表达，并确定其表达是否在氧诱导的缺血性视网膜病变过程中发生改变。 我们将比较正常、TSP 1缺陷和TSP 1过表达转基因小鼠视网膜血管的发育及其总面积。 我们将确定是否缺乏或过度表达的TSP 1影响视网膜血管的发展和新生血管的缺氧反应。鉴定TSP 1作为眼部血管形成的调节剂，并研究其在视网膜血管细胞中的作用机制，将有助于深入了解视网膜新生血管形成的缺陷。 这些知识将为开发预防和/或治疗具有新生血管成分的眼部疾病的新治疗方法提供理论基础。

DESCRIPTION (provided by applicant): Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes that are unique to this tissue. These changes include an early persistent loss of pericytes from retinal microvessels, thickening of the basement membrane, followed by hyperproliferation of endothelial cells (ECs) and abnormal vascularization of the retina, which ultimately results in blindness. Retinal vascularization is normally restricted to the superficial and deep layers of the retina. Other ocular sites such as cornea, lens, and vitreous are normally vascular free. It has been hypothesized that a negative regulator of angiogenesis is responsible for these vascular restrictions. We have recently demonstrated that thrombospondin-1 (TSP1), a potent natural inhibitor of angiogenesis, is present at ocular avascular sites and TSPt expression is dramatically down regulated with diabetes. Our hypothesis is that TSP1 is an important modulator of retinal vascular homeostasis whose alterations under pathological conditions such as diabetes and/or ischemia results in retinal neovascularization. The studies proposed here will investigate the role of TSP1 in retinal vascular development and ischemia-induced neovascularization. We will examine the expression of TSP1 in the retina and retinal capillaries during development and determine whether its expression is altered during oxygen-induced ischemic retinopathy. We will compare development of retinal vasculature and their total area in the retina of normal, TSP1 deficient, and TSP1 over-expressing transgenic mice. We will determine whether lack or over-expression of TSP1 influences retinal vascular development and neovascularization in response to hypoxia. Identification of TSP1 as a modulator of ocular vascularization and the study of its mechanisms of action in retinal vascular cells will provide insight into the defects that contribute to retinal neovascularization. This knowledge will provide the rationale for development of new therapeutic approaches for the prevention and/or treatment of ocular diseases with a neovascular component.