Complement and Pathogenic Mechanisms of AMD

AMD 的补体和致病机制

• 批准号: 8529536
• 负责人: CATHERINE BOWES RICKMAN
• 金额: $ 37.29万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529536
• 关键词: Accounting; Age related macular degeneration; Alternative Complement Pathway; Alzheimer' s Disease; Amino Acid Substitution; Amyloid; Amyloid beta-Protein; Attenuated; Blindness; Bruch' s basal membrane structure; Cholesterol; Choroid; Complement; Complement Activation; Complement Factor H; Complement Receptor; Defect; Deposition; Development; Diet; Diffuse; Disease; Disease Progression; Drusen; Elderly; Equilibrium; Eye; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Genetic Polymorphism; Health; Human; Human Development; Immunotherapy; Inflammation; Knock-out; Knockout Mice; Lead; Lipids; Maintenance; Malondialdehyde; Membrane; Modeling; Molecular; Mus; Older Population; Onset of illness; Oxidative Stress; Pathogenesis; Pathology; Phenotype; Plasma; Population; Population Attributable Risks; Predisposition; Proteins; Relative (related person); Risk; Role; Shapes; Source; Structure of retinal pigment epithelium; Testing; Transgenic Mice; Validation; Variant; Vision; Visual; aged; base; complement system; extracellular; gain of function; inhibitor/antagonist; loss of function; mouse model; new therapeutic target; novel; overexpression; prevent; risk variant; socioeconomics; 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-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.

描述（由申请人提供）：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，并且可能有助于疾病的发病机理和进展，如示例其他疾病（例如阿尔茨海默氏病）的细胞外沉积物。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享成分，这些成分部分归因于局部炎症和补体的激活 级联。 补体在AMD发病机理中的作用得到了鉴定DRUSEN中补体蛋白质的研究，并且研究涉及补体因子H（CFH）基因的变化是与AMD风险相关的最强遗传因子。 CFH变体的相关风险支持以下假设：补体级联反应的局部炎症和激活有助于AMD发病机理。 CFH多态性对整个补体系统的影响，因为它与维持眼睛的健康有关，尚不清楚，并且似乎其他触发器，调节器和/或机制与CFH协同表演似乎破坏了补体系统的精致平衡。其中突出的是淀粉样蛋白β（A？），这是子RPE沉积物的组成部分，它是补体系统的已知激活因子。我们假设RPE/BRM/脉络膜内的补体活性失调会导致RPE损伤，亚RPE沉积形成和AMD进展以及A？在该区域，有助于补体系统失调。为了支持这一假设，我们证明了一个？是治疗AMD的可行治疗靶标。对于本研究，我们开发了三种新型的小鼠模型，以检查补体在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小鼠模型中被抑制或增强（AIMS 1和2），第三个是一种新的人源化CFH小鼠，表达了CFH的正常风险或AMD风险形式（AIM 3）。每个模型具有不同的能力，可以在眼中积累活化的补体成分，从而为我们提供了补体沉积和与补体相关的表型的范围，以询问CFH在AMD中的作用。