Molecular Basis of Retinal Angiogenesis

描述（由申请人提供）：病理性眼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；致盲的主要原因分别是婴儿、工作年龄个体和老年人。它通过血管通透性增加导致视网膜水肿，血管脆弱导致出血，纤维血管增生导致牵拉和视网膜脱离，从而导致视力丧失。在这些并发症出现之前，新血管可能是无症状的。虽然血管生成往往发生在许多眼部疾病的相对较晚的阶段，但它仍然是一个非常有吸引力的治疗干预目标，因为它代表了多因素病因过程的最终共同途径，并且它是典型的直接导致视力丧失的事件。

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.