Complement System and Choroidal Neovascularization

描述（由申请人提供）：补体系统在宿主防御微生物和调节炎症反应中起关键作用。最近，有人提出，补体激活和血管增殖之间可能存在联系。视网膜相关性黄斑变性（ARMD）是西方世界55岁以上个体失明的主要原因。虽然非渗出性（干性）形式的ARMD更普遍，但灾难性视力丧失更常见于渗出性（湿性）形式，特别是脉络膜新血管形成的并发症。渗出性ARMD中新脉络膜血管形成（CNV）的发病机制知之甚少。尽管炎症与CNV的发展有关，但补体的作用尚未研究。在目前的建议中，我们希望探讨补体在脉络膜新生血管的作用，使用激光诱导的CNV的小鼠模型。使用这个模型，我们最近的研究结果表明，补体系统是中央激光诱导脉络膜血管生成的发展。因此，我们建议探索补体和补体调节蛋白在实验性CNV发展中的作用，以及使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.目的研究补体系统在激光诱导CNV小鼠模型中的作用。 2.目的研究补体调节蛋白（CRP）在激光诱导的CNV小鼠模型中的表达。 3.建立激光诱导的CNV中血管生成生长因子的补体（即MAC）依赖性和时间表达。我们相信，这些研究将导致更好地理解CNV发展中的重要潜在分子机制（即补体激活），并将有助于确定新的治疗方法的新分子靶点。

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.