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（由适用提供）：与年龄相关的黄斑变性（AMD）是全球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Bruch的膜（BRM）之间积累了细胞外脂质和富含蛋白质的沉积物。这些亚RPE沉积物可能是局灶性（drusen）或弥漫性，可能有助于疾病的发病机理和进展，类似于其他疾病的细胞间沉积物，例如阿尔茨海默氏病，动脉粥样硬化和肾小球肾炎。尽管这些疾病的分子碱基可能是多种多样的，但它们的致病沉积物包含许多共同构成，部分归因于局部炎症和完成级联的激活。鉴定在drusen中鉴定补体蛋白质的研究支持完成在AMD发病机理中的作用，并暗示完成因子H（CFH）基因的差异是与AMD风险相关的最强遗传因子。尽管有几个候选者，但AMD完成系统失调涉及的确切分子成分尚不清楚。其中包括淀粉样蛋白β（a。）和糖胺聚糖（插科打），都是drusen的成分，也是已知的完成系统调节剂。我们假设RPE/BRM/脉络膜内的补体活性失调触发了子RPE沉积的形成和AMD进展，并且该区域中的a和插科打s会影响补体替代途径。这些因素导致炎症变化，蛋白质丰富的沉积物的积累以及最终的RPE损害。为了支持这一假设，我们介绍了将A的数据确定为可行的治疗靶标，用于治疗AMD的干燥形式，目前尚无有效的疗法，并且数据表明硫酸乙酰肝素硫酸盐堵嘴调节完成。该应用将在以下三个目的中测试该假设的预测：特定目标1：测试ACLACH的去除是否会逆转视网膜/RPE畸形发生。具体目标2：测试完成系统的失调是否会加剧AMD。具体目标3：测试CFH相关的AMD风险是否通过细胞外基质的组成部分调节。 公共卫生相关性：与年龄相关的黄斑变性（AMD）是六十五岁和较大的人口不可逆视力丧失的主要原因，其社会经济伯恩的毁灭性影响不能被夸大。使用忠实地概括了人类AMD许多方面的小鼠模型，我们证明了观察到的眼部缺陷是由炎症，淀粉样蛋白β（a。）沉积和完成失调引起的 - 在人类AMD开发中实现的机制。我们提出的研究将进一步阐明完成的贡献，以及对疾病发作和进展的贡献。在AMD中，A a作为新型热目标的验证可能会导致对AMD的理解和治疗的根本范式转移。此外，阐明过度完成激活与增加的抑制对子RPE沉积形成和RPE损害的影响将有助于塑造靶向靶向的疗法的发展，从而延迟或预防AMD。最后，阐明构成后眼外基质的哪个构成的调节构成应提供其他新型AMD治疗靶标。