A mouse model and iPS cells to study hyperactive ABCA1 in the eye in age-related macular degeneration

小鼠模型和 iPS 细胞研究年龄相关性黄斑变性中过度活跃的 ABCA1

• 批准号: 10362536
• 负责人: Nicholas Lyssenko
• 金额: $ 19.22万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362536
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Adherent Culture; Adverse effects; Age related macular degeneration; Age-Months; Aging; Agreement; Alleles; Alzheimer' s Disease; Animal Model; Antibodies; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Appearance; Area; Atherosclerosis; Blood Circulation; Blood capillaries; Bruch' s basal membrane structure; Cell Culture Techniques; Cell Line; Cell membrane; Cells; Cholesterol; Choroid; Complex; Data; Deposition; Development; Diagnostic; Disease; Drusen; Environment; Exhibits; Extracellular Matrix; Exudative age-related macular degeneration; Eye; Fundus photography; Genetic study; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human Genetics; Hyperactivity; Individual; Investigation; LXRalpha protein; Lesion; Lipids; Lipoproteins; Mediating; Mifepristone; Minor; Morphology; Mus; Mutation; Oils; Pathology; Phospholipids; Plasma; Production; Protein Isoforms; Proteins; Resources; Retina; Risk; Risk Factors; Role; Side; Source; Stains; Structure; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Time; Vesicle; Virulence Factors; Water; basolateral membrane; beta catenin; experimental study; genome wide association study; geographic atrophy; human fetal retinal pigment epithelial cell; in vivo; induced pluripotent stem cell; macula; member; monolayer; mouse model; neovascularization; overexpression; particle; promoter; repository; water flow

Abstract Age-related macular degeneration (AMD) is a disease of aging that presently has very limited therapeutic resources. Soft drusen are deposits of protein and lipid between the retinal pigment epithelium (RPE) and choroidal capillaries in the Bruch's membrane. These deposits are visible in fundus photography as white to yellow patches in the macula. Their presence is a diagnostic feature of early asymptomatic AMD and a risk factor for developing late, symptomatic AMD. It was suggested over 25 years ago that drusen interfere with the flow of water and metabolites between the choroid capillaries and RPE cells and cause RPE cells either to die as in geographic atrophy and to initiate neovascularization as in wet AMD. However, the source of druse lipid has remained unknown. At various times, it was proposed that RPE plasma membrane vesicles or apolipoprotein B-lipoprotein secreted by the RPE was the source of these lesions. Recent genome-wide association studies pointed to an unexpected culprit: high-density lipoprotein (HDL). It had been known that apolipoprotein E (apo E) isoform ε4 is protective for AMD. This is the same isoform that does not mediate cell cholesterol efflux well and is a risk factor in atherosclerosis and Alzheimer's disease. But in AMD it is protective. The genome-wide association studies additionally implicated ATP-binding cassette transporter subfamily A member 1 (ABCA1) in AMD. ABCA1 mediates synthesis of HDL from lipid and apoE. ABCA1 alleles that increase plasma HDL cholesterol levels are a risk factor for AMD. Thus, increased production of HDL is an AMD rick factor. We outline reasons from druse composition and our preliminary data for the RPE and not plasma origins of HDL that is deposited in drusen. We then propose to test the hypothesis that hyperactive synthesis of HDL by the RPE contributes to druse formation. The hypothesis is tested in a mouse model of ABCA1 overexpression in the RPE in Aim 1. The hypothesis is also tested in polarized RPE monolayer cultures derived from human induced pluripotent stem cells either expressing or missing ABCA1 in Aim 2. Results of this exploratory project will provide evidence for a larger project into the role of HDL in AMD pathology.

抽象的 年龄相关性黄斑变性（AMD）是一种衰老疾病，目前治疗方法非常有限 软玻璃疣是视网膜色素上皮 (RPE) 和视网膜之间的蛋白质和脂质沉积物。 布鲁赫膜中的脉络膜毛细血管在眼底摄影中可见，呈白色至白色。 黄斑中的黄色斑块是早期无症状 AMD 的一个诊断特征，也是一种风险。 25 年前就有人提出，玻璃疣会干扰 AMD 的发展。 水和代谢物在脉络膜毛细血管和 RPE 细胞之间流动，导致 RPE 细胞死亡 如同在地图样萎缩中一样，并且在湿性AMD中启动新血管形成。然而，晶簇脂质的来源。 在不同时期，有人提出 RPE 质膜囊泡或 RPE 分泌的载脂蛋白 B 脂蛋白是这些近期全基因组损伤的根源。 关联研究指出了一个意想不到的罪魁祸首：高密度脂蛋白（HDL）。 载脂蛋白 E (apo E) 亚型 ε4 对 AMD 具有保护作用。该亚型与不介导细胞的亚型相同。 胆固醇外流良好，是动脉粥样硬化和阿尔茨海默病的危险因素，但在 AMD 中却是这样。 全基因组关联研究还表明 ATP 结合盒转运蛋白具有保护作用。 AMD 中的 A 亚家族成员 1 (ABCA1) 介导脂质和 apoE 合成 HDL。 增加血浆 HDL 胆固醇水平的等位基因是 AMD 的危险因素。 HDL 是 AMD 的一个危险因素，我们从晶簇的成分和 RPE 的初步数据中概述了原因。 而不是沉积在玻璃疣中的 HDL 的血浆来源，然后我们建议检验以下假设： RPE 过度活跃的 HDL 合成有助于晶簇形成 该假设在小鼠中得到了检验。 目标 1 中 RPE 中 ABCA1 过表达的模型。该假设也在极化 RPE 中进行了检验 来源于人诱导多能干细胞的单层培养物，表达或缺失 ABCA1 目标 2. 该探索性项目的结果将为更大的项目提供证据，以了解 HDL 在 AMD 中的作用 病理。