Complement and Pathogenic Mechanisms of AMD

描述(由申请人提供)：老年性黄斑变性(AMD)是全球视觉功能障碍的主要原因。它的特点是在视网膜色素上皮(RPE)和Bruchs膜(BRM)之间积累细胞外含脂和蛋白质的沉积物。这些亚RPE沉积可能是局灶性的(玻璃体)或弥漫性的，并可能有助于疾病的发病机制和进展，就像证明阿尔茨海默病等其他疾病的细胞外沉积一样。虽然这些疾病的分子基础可能不同，但它们的致病沉积包含许多共同的成分，这些成分部分归因于局部炎症和补体的激活。 卡斯卡德。补体在AMD发病机制中的作用得到了一些研究的支持，这些研究确定了玻璃体中的补体蛋白，并研究了补体因子H(CFH)基因的变异是与AMD风险相关的最强的遗传因素。CFH变异的相关风险支持局部炎症和补体级联激活与AMD发病有关的假说。CFH多态对整个补体系统的影响，因为它与维持眼睛的健康有关，目前还不清楚，似乎其他触发因素、调节器和/或机制可能与CFH协同作用，破坏补体系统的微妙平衡。其中最突出的是淀粉样β蛋白(A？)，它是亚RPE沉积的一种成分，是补体系统的已知激活剂。我们假设RPE/BRM/脉络膜内的补体活性失调有助于RPE损伤、亚RPE沉积的形成和AMD的进展以及A？在该地区有助于补充系统的失调。为了支持这一假设，我们证明了A？是治疗AMD的一个可行的治疗靶点。在目前的研究中，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，补体激活分别在已建立的AMD小鼠模型(目标1和2)中被抑制或增强，第三个模型是表达正常或AMD风险形式的CFH的新的人源化CFH小鼠(目标3)。每种模型都有不同的能力在眼睛中积累激活的补体成分，为我们提供了补体沉积和补体相关表型的光谱，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.