Complement and Pathogenic Mechanisms of AMD

AMD 的补体和致病机制

• 批准号: 8188337
• 负责人: CATHERINE BOWES RICKMAN
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188337
• 关键词: Affect; Age related macular degeneration; Alternative Complement Pathway; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Atherosclerosis; Blindness; Bruch' s basal membrane structure; Characteristics; Chemicals; Cholesterol; Choroid; Complement; Complement Activation; Complement Factor H; Complement Receptor; Data; Defect; Deposition; Development; Diet; Diffuse; Disease; Disease Progression; Drusen; Excision; Extracellular Matrix; Eye; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Glomerulonephritis; Glycosaminoglycans; Heparitin Sulfate; Human; Human Development; Immunotherapy; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Lead; Lipids; Modeling; Molecular; Monitor; Mus; Older Population; Onset of illness; Pathogenesis; Pathology; Phenotype; Proteins; Proteoglycan; Regulation; Retinal; Risk; Role; Shapes; Structure of retinal pigment epithelium; Susceptibility Gene; Testing; Transgenic Mice; Validation; Variant; Vision; Visual; aged; base; complement pathway; complement system; effective therapy; extracellular; feeding; in vivo; inhibitor/antagonist; loss of function; mouse model; new therapeutic target; novel; polysulfated glycosaminoglycan; prevent; socioeconomics; sulfation; therapeutic target

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.

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。其特征是视网膜色素上皮（RPE）和布鲁赫膜（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，类似于其他疾病如阿尔茨海默病、动脉粥样硬化和肾小球肾炎的细胞间沉积物特征。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级联反应的激活。 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。参与AMD补体系统失调的精确分子组分尚不清楚，尽管有几个候选者。其中包括淀粉样蛋白β（A？）和糖胺聚糖（GAG），两者都是玻璃疣的成分，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亚RPE存款形成和AMD进展，并且该区域的A？和GAG影响补体旁路途径。这些因素导致炎症变化、富含蛋白质的沉积物的积累和最终的RPE损伤。为了支持这一假设，我们提供了数据，建立A？作为治疗干性AMD的可行治疗靶点，目前还没有有效的治疗方法，并且数据显示硫酸乙酰肝素GAG调节补体。本申请将在以下三个目标中测试该假设的预测：具体目标1：测试A？的去除是否会逆转视网膜/RPE畸形。具体目标2：测试补体系统的失调是否会加剧AMD。具体目标3：测试CFH相关的AMD风险是否受细胞外基质成分的调节。 公共卫生关系：视网膜相关性黄斑变性（AMD）是65岁及以上人群中不可逆视力丧失的主要原因，其社会经济负担的破坏性影响不能被夸大。使用忠实地概括人类AMD的许多方面的小鼠模型，我们已经证明了观察到的眼部缺陷是由炎症、淀粉样蛋白β（A）沉积和补体失调引起的，这些机制与人类AMD的发展有关。我们提出的研究将进一步阐明补体和A？对疾病发作和进展的贡献。验证A作为AMD的新治疗靶点可能会导致AMD理解和治疗的根本范式转变。此外，阐明过量补体激活与增加补体抑制对亚RPE存款形成和RPE损伤的影响将有助于形成可延迟或预防AMD的补体靶向疗法的发展。最后，阐明后眼细胞外基质的哪些成分调节补体应该提供额外的新的AMD治疗靶点。