Thrombospondin-1 and retininal vascular homeostasis

描述(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中周细胞的早期持续性丢失，基底膜增厚，随后内皮细胞(ECs)过度增殖和视网膜血管形成异常，最终导致失明。视网膜血管形成通常局限于视网膜的浅层和深层。其他眼部如角膜、晶状体和玻璃体通常是无血管的。有人假设，血管生成的负调控因素是造成这些血管限制的原因。我们最近证明，凝血酶敏感蛋白-1(TSP1)，一种有效的天然血管生成抑制物，存在于眼部无血管部位，并且TSPt的表达随着糖尿病的发生而显著下调。我们的假设是TSP1是视网膜血管稳态的重要调节因子，在糖尿病和/或缺血等病理条件下，TSP1的变化会导致视网膜新生血管。本文提出的研究将探讨TSP1在视网膜血管发育和缺血诱导的新生血管形成中的作用。我们将检测TSP1在发育过程中视网膜和视网膜毛细血管中的表达，并确定其表达是否在氧诱导的缺血性视网膜病变期间发生改变。我们将比较正常、TSP1缺陷和TSP1过表达转基因小鼠的视网膜血管系统及其总面积的发育。我们将确定TSP1的缺乏或过度表达是否会影响视网膜血管发育和新生血管对低氧的反应。确认TSP1是眼血管形成的调节剂，并研究其在视网膜血管细胞中的作用机制，将有助于深入了解导致视网膜新生血管的缺陷。这一知识将为开发新的治疗方法以预防和/或治疗具有新血管成分的眼病提供理论基础。

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.