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: 7896531
• 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/7896531
• 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; Testing; TimeLine; Transgenic Mice; Validation; Variant; Vision; base; cell injury; cofactor; complement system; 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（由适用提供）：与年龄相关的黄斑变性（AMD）是一种晚期，进行性，神经退行性视网膜疾病，对以前的影响有毁灭性的影响。 AMD的发病机理显然是多因素的，其中高级年龄是强烈的已知危险因素，但其他因素，包括性别，种族，吸烟，高胆固醇血症和饮食扮演重要角色。 AMD也受特定AMD敏感性基因的影响。其中之一是编码载脂蛋白E蛋白的APOE基因是胆固醇和脂蛋白代谢的关键调节剂。另一个基因中的多态性CFH，编码补体因子H和类似H样蛋白1的蛋白质1是促进AMD易感性的主要因素，支持完成系统的关联以及与AMD的炎症。最近，我们建立了一个鼠模型，该模型通过应用三个物理相关的危险因素来概括AMD的眼病理：特定的APOE基因型，高级年龄和高脂肪/胆固醇饮食。这些小鼠会出现视网膜下色素上皮（RPE）沉积物，RPE萎缩和脉络膜新生血管形成。重要的是，这些变化需要存在所有三个风险因素。我们的分析表明，这种发病机理是由脂质转运失调，感染和淀粉样蛋白（a。）肽沉积引起的，与阿尔茨海默氏病的发病机理非常相似。在阿尔茨海默氏病中，靶向A的免疫疗法已被证明可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。因此，我们认为A也有助于AMD发病机理，并且可能是AMD中有吸引力的治疗靶标。实际上，我们的试点预防研究的结果表明，在AMD小鼠模型中靶向A的抗体可降低淀粉样蛋白伯嫩并改善疾病表型。此外，两种疾病中感染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 a和补体激活之间存在相互作用 - 我们建议A a检索具有共同依赖性并补充AMD发病机理和进展。具体而言，在本应用程序中，我们将检验以下假设：A肽沉积在AMD中激活完成，并且A a是AMD中有效的治疗靶标。目的1：测试假设的假设，即增加淀粉样蛋白伯嫩和补体失调加剧了AMD小鼠模型中AMD样病理。目的2：测试假设，即增加淀粉样蛋白的伯嫩和补体失调加剧了AMD小鼠模型中AMD样病理。目标3：为了检验以下假设：CFH变体的遗传关联会议的AMD风险与补体因子H的分子相互作用H的强度相关，补体成分3B和淀粉样淀粉样板。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。最近，我们建立了一种小鼠模型的疾病模型，该模型忠实地概括了人类AMD的病理学，并证明观察到的眼部缺陷是由脂质转运失调，感染和淀粉样β（A¿我们提出的研究将检验AMD的A肽假说，并评估A primate介质（完成）对AMD发病机理的贡献和失调的贡献。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。