AMD Model Based on Constellation of Known Human AMD Risk Factors

描述（由申请人提供）：老年性黄斑变性（AMD）是一种迟发性、进行性、神经退行性疾病，对老年人具有破坏性影响。这种疾病主要发生在65岁以上的人群中，约占西欧和北美登记失明人数的50%。AMD发展为“干性”（萎缩性）或“湿性”（渗出性）。AMD的发病机制显然是多因素的，遗传和环境因素包括衰老、吸烟、饮食、性别、氧化应激和炎症在发病和进展中起作用。我们最近通过结合AMD的三个风险因素开发了AMD的鼠模型：高龄、载脂蛋白E [apoE（蛋白质）;人APOE（基因）]同种型表达和暴露于高脂肪、高胆固醇（HF-C）饮食。这些小鼠发展出与在干性和湿性人AMD中观察到的形态学标志相似的病理学变化，包括厚的弥漫性视网膜下色素上皮（RPE）沉积物、富含脂质的玻璃疣样沉积物、布鲁赫膜增厚、覆盖感光细胞变性的RPE萎缩的斑片状区域和脉络膜新血管形成（CNV）。重要的是，这些变化需要所有三个风险因素的存在。这种自发发生的CNV动物模型是第一个纳入人类疾病的生理相关风险因素的动物模型。在这项提议中，我们的目标是开发和建立这种AMD动物模型，超越其目前记录的历史，以记录表型的再现性;将RPE，Bruch膜和脉络膜的变化与光感受器的退行性作用相关联，并确定负责这些变化的分子途径。我们期望阐明该模型中发生的变化的发病机制将有助于我们理解导致AMD神经病理学的未知分子机制。为此，我们提出了三个具体目标：（1）确定长期暴露于HF-C饮食是否增加AMD小鼠模型中自发CNV和RPE下存款形成的严重程度;（2）检查和评估APOE小鼠视网膜中的退行性和突触变化，重点是光感受器;（3）使用比较微阵列表达谱来鉴定RPE、脉络膜和视网膜中调节负责这些apoE小鼠眼中沉积物和CNV发展的途径的基因。对这些动物的分析将提供对AMD发病机制的深入了解，以及分离特定风险因素的相对贡献和退行性影响的方法。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a late-onset, progressive, neurodegenerative disease with devastating impact on the elderly. This disease occurs primarily in people over the age of 65 years and accounts for approximately 50% of registered blindness in Western Europe and North America. AMD develops as either "dry" (atrophic) or "wet" (exudative). The pathogenesis of AMD is clearly multifactorial with genetic and environmental factors including aging, smoking, diet, gender, oxidative stress, and inflammation playing roles in onset and progression. We have recently developed a murine model of AMD by combining three of the risk factors for AMD: advanced age, apolipoprotein E [apoE (protein); human APOE (gene)] isoform expression and exposure to a high- fat, high-cholesterol (HF-C) diet. These mice develop pathological changes similar to the morphologic hallmarks observed in dry and wet human AMD, including thick diffuse sub-retinal pigment epithelium (RPE) deposits, lipid- rich drusen-like deposits, thickening of Bruch's membrane, patchy regions of RPE atrophy overlying photoreceptor degeneration and choroidal neovascularization (CNV). Importantly, these changes require the presence of all three risk factors. This animal model of spontaneously-occurring CNV is the first to incorporate physiologically-relevant risk factors of human disease. In this proposal, we aim to develop and establish this animal model of AMD, beyond its currently documented history, to document the reproducibility of the phenotype; to correlate changes in the RPE, Bruch's membrane and choroid to degenerative effects in the photoreceptors and to identify molecular pathways responsible for these changes. We expect that elucidation of the pathogenesis of the changes that occur in this model will contribute to our understanding of unknown molecular mechanisms leading to the neuropathology of AMD. To this end, we propose three Specific Aims: (1) Determine whether prolonged exposure to a HF-C diet increases severity of spontaneous CNV and sub-RPE deposit formation in a mouse model of AMD; (2) Examine and evaluate degenerative and synaptic changes in the retina in APOE mice with a focus on photoreceptors; (3) to identify genes in the RPE, choroid and retina that regulate pathways responsible for the development of deposits and CNV in the eyes of these apoE mice, using comparative microarray expression profiling. Analysis of these animals will provide insight into the pathogenesis of AMD as well as a means to separate the relative contribution and degenerative effects of specific risk factors.