The APOE TR Mouse: A Model for Elucidating Pathogenic Mechanisms of AMD

APOE TR 小鼠：阐明 AMD 致病机制的模型

• 批准号: 7506287
• 负责人: CATHERINE BOWES RICKMAN
• 金额: $ 35.1万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7506287
• 关键词: A Mouse; Affinity; Age related macular degeneration; Alternative Complement Pathway; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Animals; Antibodies; Apolipoprotein E; Atrophic; Attenuated; Autopsy; Binding; Biochemical; Biological Assay; Blindness; Cells; Cholesterol; Choroid; Choroidal Neovascularization; Code; Cognition; Complement; Complement 3b; Complement Activation; Complement Factor H; Complex; Defect; Dependence; Deposition; Diet; Disease; E protein; Elderly; Electroretinography; Ethnic Origin; Etiology; Eye; Fatty acid glycerol esters; Fluorescein Angiography; Fundus; Gender; Genes; Genetic Polymorphism; Genotype; Human; Human Pathology; Immune response; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammation Mediators; Intervention Studies; Lead; Length; Liquid substance; Literature; Measures; Metabolism; Modeling; Mono-S; Mus; Nerve Degeneration; Ocular Pathology; Older Population; Outcome; Outcome Measure; Pathogenesis; Pathology; Pathway interactions; Peptides; Phase; Play; Predisposition; Prevention; Proteins; Regulation; Relative (related person); Retina; Retinal Diseases; Risk; Risk Factors; Role; Severities; Smoke; Smoking; Structure of retinal pigment epithelium; Susceptibility Gene; System; Testing; TimeLine; Transgenic Mice; Validation; Variant; Vision; base; cell injury; cofactor; disease phenotype; genetic association; hypercholesterolemia; in vivo; lipid transport; lipoprotein cholesterol; mouse crry protein; mouse model; new therapeutic target; overexpression; peptide A; public health relevance; socioeconomics; therapeutic target

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a late-onset, progressive, neurodegenerative retinal disease with devastating impact on the elderly. The pathogenesis of AMD is clearly multifactorial in which advanced age is the strongest known risk factor, but other factors including gender, ethnicity, smoking, hypercholesterolemia, and diet play important roles. AMD is also influenced by specific AMD-susceptibility genes. One of these is the APOE gene coding for the apolipoprotein E protein a key regulator of cholesterol and lipoprotein metabolism. Polymorphisms in another gene, CFH, coding for complement factor H and factor H-like protein 1, is a major contributor to AMD susceptibility, supporting an association of the complement system and inflammation with AMD. Recently, we established a murine model that recapitulates ocular pathologies of AMD by applying three physiologically relevant risk factors: specific APOE genotype, advanced age and high fat/cholesterol-rich diet. These mice develop sub-retinal pigment epithelium (RPE) deposits, RPE atrophy and choroidal neovascularization. Importantly, these changes require the presence of all three risk factors. Our analyses suggest this pathogenesis arises from lipid transport dysregulation, inflammation and amyloid ¿ (A¿) peptide deposition, strikingly similar to the pathogenesis of Alzheimer's disease. In Alzheimer's disease, immunotherapy targeting A¿ has been shown to reduce the number of amyloid deposits and enhance cognition in humans and animal models. Therefore we propose that A¿ also contributes to AMD pathogenesis and may be an attractive therapeutic target in AMD. Indeed, the results of our pilot prevention studies indicate that antibody targeting of A¿ in our AMD mouse model reduces amyloid burden and ameliorates the disease phenotype. Furthermore, the overlap of inflammation and amyloid in both diseases suggests that components of the innate immune response (namely, complement) interact directly with A¿ in AMD. In addition, consistent with the Alzheimer's disease literature - that there is an interaction between A¿ and complement activation - we propose that there is a co-dependence of A¿ and complement in AMD pathogenesis and progression. Specifically, in this application we will test the hypothesis that A¿ peptide deposition activates complement in AMD, and that A¿ is a valid therapeutic target in AMD. Aim 1: To test the hypothesis that increased amyloid burden and complement dysregulation exacerbates AMD-like pathologies in a mouse model of AMD. Aim 2: To test the corollary hypothesis that decreased amyloid ameliorates AMD-like pathologies in a mouse model of AMD. Aim 3: To test the hypothesis that the genetic association of CFH variants conferring risk of AMD is correlates with the strength of to the molecular interaction of complement factor H, complement component 3b and amyloid ¿. 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. Recently, we have established a mouse model of the disease that faithfully recapitulates the pathology of human AMD and have demonstrated that the observed ocular defects arise from lipid transport dysregulation, inflammation and amyloid beta (A¿) peptide deposition - mechanisms strikingly similar to those proposed as the etiology of Alzheimer's disease. Our proposed studies will test the A¿ peptide hypothesis of AMD and evaluate the contribution of A¿ and dysregulation of the inflammatory mediator, complement, to AMD pathogenesis. Validation of A¿ as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD.

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是一种迟发性、进行性、神经退行性视网膜疾病，对老年人具有毁灭性影响。 AMD 的发病机制显然是多因素的，其中高龄是已知最强的危险因素，但其他因素，包括性别、种族、吸烟、高胆固醇血症和饮食也发挥着重要作用。 AMD 还受到特定 AMD 易感基因的影响。其中之一是编码载脂蛋白 E 的 APOE 基因，载脂蛋白 E 是胆固醇和脂蛋白代谢的关键调节因子。另一个基因 CFH（编码补体因子 H 和因子 H 样蛋白 1）的多态性是 AMD 易感性的一个主要因素，支持补体系统和炎症与 AMD 之间的关联。最近，我们建立了一个小鼠模型，通过应用三个生理相关的危险因素来概括 AMD 的眼部病理：特定的 APOE 基因型、高龄和高脂肪/富含胆固醇的饮食。这些小鼠出现视网膜下色素上皮 (RPE) 沉积、RPE 萎缩和脉络膜新生血管形成。重要的是，这些变化需要所有三个风险因素都存在。我们的分析表明，这种发病机制源于脂质转运失调、炎症和淀粉样蛋白 ¿ (A¿) 肽沉积，与阿尔茨海默病的发病机制惊人地相似。在阿尔茨海默病中，针对 A 的免疫疗法已被证明可以减少淀粉样蛋白沉积的数量并增强人类和动物模型的认知能力。因此，我们认为 A¿ 也有助于 AMD 发病机制，并且可能是 AMD 有吸引力的治疗靶点。事实上，我们的初步预防研究结果表明，在我们的 AMD 小鼠模型中，针对 A¿ 的抗体可减少淀粉样蛋白负担并改善疾病表型。此外，两种疾病中炎症和淀粉样蛋白的重叠表明先天免疫反应的成分（即补体）直接与 AMD 中的 A 相互作用。此外，与阿尔茨海默氏病文献一致 - A¿ 和补体激活之间存在相互作用 - 我们提出 A¿ 和补体在 AMD 发病机制和进展中存在相互依赖性。具体来说，在本申请中，我们将测试以下假设：A¿ 肽沉积激活 AMD 中的补体，并且 A ¿ 是 AMD 的有效治疗靶点。目标 1：在 AMD 小鼠模型中检验淀粉样蛋白负荷增加和补体失调会加剧 AMD 样病理的假设。目标 2：在 AMD 小鼠模型中检验淀粉样蛋白减少可改善 AMD 样病理的推论假设。目标 3：检验以下假设：导致 AMD 风险的 CFH 变异的遗传关联与补体因子 H、补体成分 3b 和淀粉样蛋白 ¿ 的分子相互作用的强度相关。公共健康相关性：年龄相关性黄斑变性 (AMD) 是 65 岁及以上人群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怎么强调也不为过。最近，我们建立了该疾病的小鼠模型，忠实地再现了人类 AMD 的病理学，并证明观察到的眼部缺陷是由脂质转运失调、炎症和淀粉样蛋白 β (A¿) 肽沉积引起的，这些机制与阿尔茨海默病的病因学惊人相似。我们提出的研究将测试 AMD 的 A¿ 肽假说，并评估 A¿ 和炎症介质补体失调对 AMD 发病机制的贡献。验证 A¿ 作为 AMD 的新治疗靶点可能会导致对 AMD 的理解和治疗发生根本性的范式转变。