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.

摘要 老年性黄斑变性(AMD)是一种老年性疾病，目前的治疗方法非常有限 资源。软性玻璃体是位于视网膜色素上皮(RPE)和视网膜色素上皮(RPE)之间的蛋白质和脂肪沉积 Bruch膜中的脉络膜毛细血管。这些沉积物在眼底照相中可见为白色至白色。 黄斑上有黄色斑块。它们的存在是早期无症状AMD的一个诊断特征，也是一种风险 导致晚期、症状性AMD的因素。25年前就有人提出，杜松子酒会干扰 水和代谢产物在脉络膜毛细血管和RPE细胞之间流动，导致RPE细胞死亡 如在地理萎缩和启动新生血管，如在湿性AMD。然而，德鲁兹脂类的来源 一直不为人所知。在不同时期，有人提出RPE质膜囊泡或 RPE分泌的载脂蛋白B-脂蛋白是这些损害的来源。最新全基因组 协会研究指出了一个意想不到的罪魁祸首：高密度脂蛋白(HDL)。人们已经知道， 载脂蛋白E(Apo E)亚型ε4对AMD具有保护作用。这是不参与细胞调节的相同异构体 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中是这样的 防护性的。全基因组关联研究还涉及到ATP结合盒转运体 AMD的A亚家族成员1(ABCA1)。ABCA1介导脂质和载脂蛋白E合成高密度脂蛋白。ABCA1 增加血浆高密度脂蛋白水平的等位基因是AMD的危险因素。因此，增加的产量 高密度脂蛋白是AMD的一个重要影响因素。我们概述了德鲁兹成分的原因和我们对RPE的初步数据 而不是沉积在玻璃体中的高密度脂蛋白的血浆来源。然后，我们建议检验这个假设 RPE对高密度脂蛋白的过度合成有助于德鲁斯的形成。这一假设在一只小鼠身上得到了验证。 ABCA1在AIM 1的RPE中过表达的模型。该假说在极化的RPE中也得到了验证 表达或缺失ABCA1的人诱导多能干细胞的单层培养 目的2.这个探索性项目的结果将为一个更大的项目提供证据，以研究高密度脂蛋白在AMD中的作用 病理学。