Complement System and Choroidal Neovascularization

描述(申请人提供)：目前建议的长期目标是找到治疗老年性黄斑变性(AMD)的方法，AMD是西方世界老年人不可逆转失明的主要原因。脉络膜新生血管(CNV)是湿性AMD的特征，是导致中心视力突然丧失和致残的原因。不幸的是，目前AMD患者可用的治疗方案由于其短期和严重的副作用而受到限制。因此，需要进一步的研究，以预防AMD，延缓其进展，并开发有效的治疗策略。大量证据支持补体在人类和实验性AMD的发病机制中的作用。我们的研究表明，通过激活替代途径形成的膜攻击复合体(MAC)对于促进激光诱导的小鼠CNV发展的生长因子的释放是必不可少的。我们还发现，在激光诱导的CNV生长过程中，替代途径的主要调节因子H的表达下调。在目前的方案中，我们希望在激光诱导的CNV过程中建立MAC形成与眼内因子H水平的依赖关系。我们的结果进一步表明，CD59对MAC形成的调控在激光诱导的CNV的发展中起着至关重要的作用。因此，我们建议探索重组的膜靶向CD59对CNV复合体生长的影响。多种细胞因子和趋化因子被认为在AMD的发病机制中起作用，一些研究表明这些分子的表达受MAC的存在的影响。本研究旨在探讨激光诱导CNV小鼠模型中MAC、细胞因子/趋化因子与生长因子的关系。这项建议的具体目标是： 1.探讨补体替代途径的关键调节因子H在激光诱导的CNV中的作用--H因子与MAC形成的关系。 2.探讨重组膜靶向MAC调节剂CD59对激光诱导的CNV的治疗作用。 3.分析激光诱导的新生血管中MAC、细胞因子/趋化因子与血管生长因子的关系。 我们认为，拟议的研究对于深入了解湿性AMD的发病机制以及相关的危险因素是至关重要的。此外，这些研究将极大地有助于开发基于补体激活终末阶段选择性抑制的AMD有效治疗方法。

DESCRIPTION (provided by applicant): Long-term objective of the current proposal is to find a cure for age-related macular degeneration (AMD), which is the leading cause of irreversible blindness in the Western world among the elderly. Choroidal neovascularization (CNV) is the hallmark of wet AMD, and is responsible for the sudden and disabling loss of central vision. Unfortunately, treatment options currently available to AMD patients have limitations due to their short-term and serious side effects. Therefore, future investigations are needed so that AMD could be prevented, its progression be delayed and effective therapeutic strategies could be developed. A substantial body of evidence supports a role of complement in the pathogennesis of both human and experimental AMD. Our studies have demonstrated that the formation of membrane attack complex (MAC) via the activation of alternative pathway was essential for the release of growth factors that drive the development of laser- induced CNV in mice. We have also shown that the expression of factor H, the major regulator of the alternative pathway was down-regulated during the growth of laser-induced CNV. In the current proposal we wish to establish the dependence of MAC formation on factor H levels within the eye during laser-induced CNV. Our results further demonstrated that regulation of MAC formation by CD59 plays a crucial role in the development of laser-induced CNV. Thus, we propose to explore the effect of recombinant, membrane- targeted CD59 on the growth of CNV complex. Various cytokines and chemokines have been suggested to play a role in AMD pathogenesis and several studies have suggested that the expression of these molecules is affected by the presence of MAC. In the current proposal we intend to investigate the relationship between MAC, cytokines/chemokines and growth factors in mouse model of laser-induced CNV. The specific aims of this proposal are: 1. To investigate the role of factor H, the key regulator of alternative complement pathway in laser- induced CNV - Relationship between factor H and MAC formation. 2. To explore the therapeutic potential of recombinant membrane-targeted form of MAC regulator CD59 in laser-induced CNV. 3. To analyze the relationship between MAC, cytokines/chemokines and angiogenic growth factors in laser-induced CNV. We believe that the proposed studies are essential to gain insights into the pathogenesis as well as the risk factors associated with wet-AMD. Furthermore, these studies will be immensely helpful in the development of effective therapy for AMD based on selective inhibition at the terminal stage of complement activation.