Complement System and Choroidal Neovascularization

描述(申请人提供)：补体系统在宿主对微生物的防御和炎症反应的调节中发挥关键作用。最近，有研究表明，补体激活和血管增殖之间可能存在联系。年龄相关性黄斑变性(ARMD)是西方世界55岁以上人群失明的主要原因。尽管非渗出型(干型)ARMD更为常见，但渗出型(湿型)更易导致灾难性视力丧失，尤其是脉络膜新生血管并发症。渗出型ARMD中新的脉络膜血管形成(CNV)的发病机制尚不清楚。虽然炎症与CNV的发生有关，但补体的作用尚未被探讨。在目前的方案中，我们希望利用激光诱导的CNV小鼠模型来探索补体在脉络膜新生血管中的作用。利用这个模型，我们最近的结果表明，补体系统在激光诱导的脉络膜血管生成的发展中起着中心作用。因此，我们建议探讨补体和补体调节蛋白在实验性CNV发生发展中的作用，以及利用可溶性补体调节蛋白抑制补体的治疗效果。这项建议的具体目标是： 1.研究激光诱导的小鼠CNV模型的补体系统。 2.研究补体调节蛋白(CRPS)在激光诱导小鼠CNV模型中的作用。 3.建立激光诱导的新生血管中血管生长因子的补体(即MAC)依赖性和时间性表达。我们相信，这些研究将有助于更好地了解CNV发生发展的一个重要的潜在分子机制(即补体激活)，并将有助于为新的治疗方法确定新的分子靶点。

DESCRIPTION (provided by applicant): The complement system plays a critical role in the host defense against microorganisms and in the modulation of inflammatory responses. Recently, it has been suggested that there may be a link between complement activation and vascular proliferation. Age-related macular degeneration (ARMD) is the leading cause of blindness in the Western world in individuals over 55 years of age. Although the nonexudative (dry) form of ARMD is more prevalent, catastrophic vision loss is more frequently associated with the exudative (wet) form, specifically from the complications of neovascularization of the choroid. The pathogenesis of new choroidal vessel formation (CNV) in exudative ARMD is poorly understood. Although inflammation has been implicated in the development of CNV the role of complement has not been explored. In the current proposal we wish to explore the role of complement in choroidal neovascularization using the mouse model of laser-induced CNV. Using this model, our recent results suggest that the complement system is central to the development of laser-induced choroidal angiogenesis. Thus, we propose to explore the role of complement and complement regulatory proteins in the development of experimental CNV, as well as the treatment effect of complement inhibition using soluble complement regulatory proteins. The specific aims of this proposal are: 1. To study the complement system in the mouse model of laser-induced CNV. 2. To study complement regulatory proteins (CRPs) in the mouse model of laser-induced CNV. 3. To establish the complement (i.e. MAC) dependence and temporal expression of angiogenic growth factors in laser-induced CNV. We believe that these studies will lead to a better understanding of an important underlying molecular mechanism in the development of CNV (i.e. complement activation), and will help to identify new molecular targets for novel therapeutic approaches.