Retinopathy of prematurity: Understand its pathogenesis

新生儿技术的新发展使出生时视网膜血管发育受限的较小婴儿存活下来，因此更容易患早产儿视网膜病变(ROP)。据推测，随着越来越多和更小的早产儿存活下来，除非找到有效的治疗方法，否则ROP导致的视力损失的发生率将继续增加。晚期ROP的特征是视网膜血管的无节律生长。这种生长是通过一种称为血管生成的过程发生的，这表明新的血管是由现有血管的异常萌芽形成的。血管生成导致的视力丧失并不是ROP独有的；总体而言，具有这种特征的眼部疾病构成了美国失明的主要原因。旨在了解其中一种疾病的动物模型中视网膜血管生成的研究的意义因将新知识应用于其他与血管生成起作用的眼部疾病的可能性而得到放大。这个项目的最终目标是基于对相关模型的研究所获得的理解，开发预防视网膜血管生成的方法。我们建议使用纯培养的视网膜微血管内皮细胞(RMEC)，一个成熟的ROP大鼠模型和一个目前正在完善的ROP小鼠模型。通过这些工具，我们将解决以下四个相互关联的目标：1)研究一个关键的酪氨酸激酶，Src，在RMEC增殖和管形成以及与ROP相关的视网膜血管生成中的作用；2)表征ROP相关的视网膜血管生成的蛋白分解方面，重点是PAI-1、MMP-2和-9以及TIMP-2；3)表征Angiopoietins 1和2在视网膜血管生成和血管生成中的作用；以及确定导致穿透性眼部损伤的血管抑制效应的因素。

New developments in neonatal technology have resulted in the survival of smaller infants who have limited retinal vascular development at birth and, thus, greater susceptibility to retinopathy of prematurity (ROP). It is reasoned that as more and smaller premature babies survive, the incidence of visual loss from ROP will continue to increase unless effective treatments are found. Advanced ROP is characterized by a period of unregulated growth of retinal blood vessels. This growth occurs by a process known as angiogenesis, indicating that the new vessels form by an abnormal sprouting of exiting vessels. The loss of vision from angiogenesis is not unique to ROP; collectively, ocular disorders with this feature constitute the leading cause of blindness in the U.S. The significance of research aimed at understanding retinal angiogenesis in an animal model of one of these diseases is amplified by the potential of applying the new knowledge to other ocular conditions in which angiogenesis plays a role. The ultimate goal of this project is to develop methods to prevent retinal angiogenesis based upon understanding gained from studies of relevant models. We propose to use pure cultures of retinal microvascular endothelial cells (RMEC), a well- established rat model of ROP and a mouse model of ROP currently under refinement. With these tools, we will address the following four interrelated aims: 1) investigation of the role of a pivotal tyrosine kinase, Src, in RMEC proliferation and tube formation and in ROP-related retinal angiogenesis; 2) characterization of the proteolytic aspect of ROP-related retinal angiogenesis, emphasizing PAI-1, MMP-2 and -9 and TIMP-2; 3) characterization of the roles of angiopoietins 1 and 2 in retinal vasculogenesis and angiogenesis; and identification of factors responsible for the angiostatic effect of penetrating ocular injury.