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）：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。其特征是视网膜色素上皮（RPE）和布鲁氏膜（Bruch’s membrane, BrM）之间的细胞外含脂和含蛋白沉积物的积累。这些亚rpe沉积可能是局灶性的或弥漫性的，并且可能导致疾病的发病和进展，如记录的其他疾病如阿尔茨海默病的细胞外沉积。尽管这些疾病的分子基础可能是多种多样的，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的激活