Complement and Pathogenic Mechanisms of AMD

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是世界范围内视觉功能障碍的主要原因。其特征在于视网膜色素上皮（RPE）和布鲁赫膜（Bruch's membrane，BrM）之间的细胞外含脂质和蛋白质的沉积物的积累。这些亚RPE沉积物可以是局灶性的（玻璃疣）或弥漫性的，并且可能有助于疾病发病机制和进展，如对于导致其他疾病如阿尔茨海默病的细胞外沉积物所记录的。虽然这些疾病的分子基础可能是不同的，但它们的致病性沉积物含有许多共同的成分，这些成分部分归因于局部炎症和补体激活 级联。 补体在AMD发病机制中的作用得到了以下研究的支持：鉴定玻璃疣中的补体蛋白的研究，以及暗示补体因子H（CFH）基因变异作为与AMD风险相关的最强遗传因子的研究。CFH变异体的相关风险支持了局部炎症和补体级联激活有助于AMD发病机制的假设。CFH多态性对整个补体系统的影响，因为它涉及到维持眼睛的健康，还没有得到很好的理解，似乎可能是其他触发器，调节剂和/或机制与CFH一起作用，破坏补体系统的微妙平衡。其中最突出的是淀粉样蛋白β（A？），是一种已知的补体系统激活剂的亚RPE沉积物的成分。我们推测RPE/BrM/脉络膜内补体活性失调导致RPE损伤、亚RPE存款形成和AMD进展，A？在这个区域有助于补充系统失调。在支持这一假设，我们表明，A？是治疗AMD的可行治疗靶点。在本研究中，我们开发了三种新的小鼠模型来研究补体在AMD发展中的作用。在前两个模型中，补体激活在建立的AMD小鼠模型中分别被抑制或增强（目的1和2），第三个是表达CFH的正常或AMD风险形式的新的人源化CFH小鼠（目的3）。每种模型在眼睛中积累活化的补体成分的能力不同，为我们提供了补体沉积和补体相关表型的谱，以询问CFH在AMD中的作用。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. It is characterized by the accumulation of extracellular lipid- and protein-containing deposits between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and are likely to contribute to disease pathogenesis and progression as documented for extracellular deposits that exemplify other diseases such as Alzheimer's disease. Although the molecular bases of these diseases may be diverse, their pathogenic deposits contain many shared constituents that are attributable, in part, to local inflammation and activation of the complement cascade. The role of complement in AMD pathogenesis is supported by studies identifying complement proteins in drusen and studies implicating variations in the complement factor H (CFH) gene as the strongest genetic factor associated with AMD risk. The associated risk of CFH variants supports the hypothesis that local inflammation and activation of the complement cascade contributes to AMD pathogenesis. The repercussions of the CFH polymorphism on the entire complement system, as it pertains to the maintenance of the health of the eye, are not yet well understood and it seems likely that other triggers, modulators and/or mechanisms act in concert with CFH in disrupting the delicate equilibrium of the complement system. Prominent among these is amyloid beta (A?), a constituent of sub-RPE deposits, which is a known activator of the complement system. We hypothesize that dysregulated complement activity within the RPE/BrM/choroid contributes to RPE damage, sub-RPE deposit formation and AMD progression and A? in this region contributes to complement system dysregulation. In support of this hypothesis, we showed that A? is a viable therapeutic target in the treatment of AMD. For the present study, we have developed three novel mouse models to examine the role of complement in the development of AMD. In the first two models complement activation is suppressed or augmented, respectively, in an established AMD mouse model (Aims 1 and 2) and the third is a new humanized CFH mouse expressing either the normal or AMD risk form of CFH (Aim 3). Each model has a different capacity to accumulate activated complement components in the eye providing us a spectrum of complement deposition and complement-related phenotypes to interrogate the role of CFH in AMD.