Complement System and Choroidal Neovascularization

描述（由申请人提供）：目前提案的长期目标是找到治疗老年性黄斑变性（AMD）的方法，这是西方世界老年人不可逆失明的主要原因。脉络膜新生血管（CNV）是湿性AMD的标志，并且是导致中心视力突然丧失和致残的原因。不幸的是，目前可用于AMD患者的治疗选择由于其短期和严重的副作用而具有局限性。因此，需要进一步的研究，以预防AMD，延缓其进展，并制定有效的治疗策略。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，通过激活旁路途径形成膜攻击复合物（MAC）是驱动激光诱导的小鼠CNV发展的生长因子释放所必需的。我们还发现，在激光诱导的CNV生长过程中，旁路途径的主要调节因子H的表达下调。在目前的建议中，我们希望建立依赖于MAC的形成在眼睛内的H因子水平在激光诱导的CNV。我们的研究结果进一步表明，MAC的形成由CD 59的调节起着至关重要的作用，在激光诱导的CNV的发展。因此，我们建议探索重组的、膜靶向的CD 59对CNV复合物生长的影响。各种细胞因子和趋化因子已被认为在AMD发病机制中起作用，并且一些研究表明这些分子的表达受到MAC存在的影响。在本研究中，我们将探讨激光诱导的CNV小鼠模型中MAC、细胞因子/趋化因子和生长因子之间的关系。这项建议的具体目标是： 1.探讨补体旁路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形成之间的关系。 2.探讨重组膜靶向MAC调节因子CD 59对激光诱导的CNV的治疗潜力。 3.分析MAC、细胞因子/趋化因子和血管生成因子在激光诱导CNV中的关系。 我们认为，这些研究对于深入了解湿性AMD的发病机制和危险因素至关重要。此外，这些研究将极大地有助于开发基于在补体激活的终末阶段选择性抑制的AMD的有效疗法。

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.