Complement and Pathogenic Mechanisms of AMD

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是世界范围内视觉功能障碍的主要原因。它的特征是在视网膜色素上皮（RPE）和布鲁赫膜（Bruch’s membrane, BrM）之间积累细胞外富含脂质和蛋白质的沉积物。这些亚rpe沉积可能是局灶性的或弥漫性的，并可能导致疾病的发病和进展，类似于阿尔茨海默病、动脉粥样硬化和肾小球肾炎等其他疾病的细胞间沉积特征。尽管这些疾病的分子基础可能多种多样，但它们的致病沉积物包含许多共同的成分，这些成分部分可归因于局部炎症和补体级联的激活。补体在AMD发病机制中的作用得到了一些研究的支持，这些研究发现了drusen中的补体蛋白，并表明补体因子H （CFH）基因的变异是与AMD风险相关的最强遗传因素。AMD中补体系统失调的确切分子成分尚不清楚，尽管有几种候选成分。其中包括淀粉样蛋白（A¿）和糖胺聚糖（GAGs），它们都是蛋白的成分，也是已知的补体系统调节剂。我们假设RPE/BrM/脉络膜内补体活性失调触发了subpe沉积形成和AMD进展，并且该区域的A¿和GAGs影响补体替代途径。这些因素导致炎症改变、富含蛋白质的沉积物积聚，最终导致RPE损伤。为了支持这一假设，我们提供的数据表明A¿是治疗干型AMD的可行治疗靶点，目前尚无有效的治疗方法，并且数据显示硫酸肝素GAGs调节补体。此应用程序将在以下三个目标中测试该假设的预测：具体目标1：测试去除A¿是否会逆转视网膜/RPE畸形发生。特异性目的2：测试补体系统失调是否会加重AMD。特异性目标3：测试cfh相关的AMD风险是否受到细胞外基质成分的调节。

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-rich deposits between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and likely contribute to disease pathogenesis and progression similar to intercellular deposits characteristic of other diseases like Alzheimer's disease, atherosclerosis, and glomerulonephritis. 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 risk for AMD. The precise molecular components involved in dysregulation of the complement system in AMD are unknown, although there are several candidates. Among these are amyloid beta (A¿) and glycosaminoglycans (GAGs), both constituents of drusen, and known modulators of the complement system. We hypothesize that dysregulated complement activity within the RPE/BrM/choroid triggers subRPE deposit formation and AMD progression and that A¿ and GAGs in this region affect the complement alternative pathway. These factors contribute to inflammatory changes, accumulation of protein- rich deposits and ultimately RPE damage. In support of this hypothesis, we present data establishing A¿ as a viable therapeutic target for treatment of the dry form of AMD, for which there are currently no effective therapies, and data showing that heparan sulfate GAGs regulate complement. This application will test predictions of this hypothesis in the following three aims: Specific Aim 1: Test whether removal of A¿ will reverse retinal/RPE dysmorphogenesis. Specific Aim 2: Test whether dysregulation of the complement system will exacerbate AMD. Specific Aim 3: Test whether CFH-associated AMD risk is modulated by components of the extracellular matrix. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the sixty-five-and-older population, and the devastating impact of its socioeconomic burden cannot be overstated. Using mouse models that faithfully recapitulate many aspects of human AMD, we have demonstrated that observed ocular defects arise from inflammation, amyloid beta (A¿) deposition and complement dysregulation - mechanisms implicated in development of human AMD. Our proposed studies will further clarify the contribution of complement and A¿ to disease onset and progression. Validation of A¿ as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD. Moreover, unraveling the impact of excess complement activation versus increased complement inhibition on subRPE deposit formation and RPE damage will help shape the development of complement-targeted therapies that could delay or prevent AMD. Finally, elucidating which constituents of the posterior eye extracellular matrix regulate complement should provide additional novel AMD therapy targets.