Molecular Basis of Retinal Angiogenesis

描述（由申请人提供）：病理性眼部血管生成发生在早产儿视网膜病变、增殖性糖尿病视网膜病变和年龄相关性黄斑变性中;分别是婴儿、工作年龄个体和老年人失明的主要原因。它通过增加血管渗透性导致视网膜水肿、血管脆性导致出血和纤维血管增生伴牵引性视网膜脱离而导致视力丧失。新血管可能无症状，直到这些并发症的发展。尽管血管生成倾向于发生在许多眼部疾病过程中的相对晚期，但它仍然是治疗干预的高度有吸引力的靶点，因为它代表了病因学中多因素过程中的最终共同途径，并且它是通常直接导致视力丧失的事件。 本项目的最终目标是基于从相关模型研究中获得的理解，开发预防眼部血管生成的方法。我们建议使用纯培养的Muller细胞和视网膜微血管内皮细胞（RMEC），以及小鼠和大鼠模型的氧诱导的视网膜病变（OIR）。利用这些工具，我们将实现三个相互关联的目标：目的1）我们将研究前列腺素类在缺氧诱导的Muller细胞产生VEGF中的作用：目的2）我们将研究前列腺素类在VEGF刺激的RMEC血管生成反应中的作用;（3）以目标1和2为指导，我们会把研究扩展至建立了视网膜血管生成的动物模型，其中前列腺素类合成和活性的特定靶点将被操纵，遗传的在每种情况下，我们将遵循经典的功能丧失/功能获得实验策略。

DESCRIPTION (provided by applicant): Pathological ocular angiogenesis occurs in retinopathy of prematurity, proliferative diabetic retinopathy and age-related macular degeneration; the leading causes of blindness in infants, working age individuals and the elderly, respectively. It causes visual loss through increased vascular permeability leading to retinal edema, vascular fragility resulting in hemorrhage, and fibrovascular proliferation with tractional and retinal detachment. New vessels may be asymptomatic until these complications develop. Although angiogenesis tends to occur at a relatively late stage in the course of many ocular disorders, it is nonetheless a highly attractive target for therapeutic intervention, since it represents a final common pathway in processes that are multifactorial in etiology, and it is the event that typically leads directly to visual loss. The ultimate goal of this project is to develop methods to prevent ocular angiogenesis based upon understanding gained from studies of relevant models. We propose to use pure cultures of Muller cells and retinal microvascular endothelial cells (RMEC), as well as mouse and rat models of oxygen-induced retinopathy (OIR). With these tools, we will address three interrelated aims: Aim 1) we will examine of the role of prostanoids in hypoxia-induced VEGF production by Muller cells; Aim 2) we will examine the role of prostanoids in VEGF-stimulated angiogenic responses of RMEC; 3) using aims 1 and 2 as guides, we will extend the studies to well-established animal models of retinal angiogenesis where specific targets of prostanoid synthesis and activity will be manipulated pharmacologically or genetically. In each case, we will follow classic loss-of-function/gain-of-function experimental strategies.