Soft drusen in rhesus macaques as a nonhuman primate model of early age-related macular degeneration

恒河猴的软玻璃疣作为早期年龄相关性黄斑变性的非人类灵长类动物模型

基本信息

批准号：
10547804
负责人：
Glenn Yiu
金额：
$ 68.48万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10547804
关键词：
Age Age related macular degeneration Animal Model Animals Apolipoprotein E Apolipoproteins Apolipoproteins B Arterial Fatty Streak Binding Bioinformatics Blindness Body Weight Body Weights and Measures Body fat California Cardiovascular Diseases Cells Cholesterol Cholesterol Esters Choroid Complement Complement Membrane Attack Complex Contralateral Deposition Development Diet Dietary Fats Dose Drusen Elderly Epidemiology Euthanasia Evolution Exposure to Eye Fasting Fatty acid glycerol esters Fundus Gene Expression Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Glial Fibrillary Acidic Protein Goals Growth Health Heterogeneity High Density Lipoproteins High Fat Diet Histologic Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Image Imaging technology Immune Immunohistochemistry Inflammatory Response Intervention Laboratory Animals Lipids Lipofuscin Lipoproteins Low-Density Lipoproteins Macaca Macaca mulatta Macrophage Activation Mammals Measures Metabolic Modeling Molecular Multimodal Imaging National Institute on Aging Oils Optical Coherence Tomography Oral Pathogenesis Pathway interactions Patients Phenotype Pilot Projects Placebos Plasma Prevalence Primates Research Resolution Retina Risk Factors Role Serum Simvastatin Smoking Structure of retinal pigment epithelium Surveys Susceptibility Gene Testing Tissues Transferase Triglycerides aged atorvastatin cohort cost dietary genetic variant genome sequencing hepatic lipase imaging capabilities in vivo in vivo imaging insight lipid metabolism lipoprotein lipase mRNA Expression macroglia macula multimodality new therapeutic target next generation sequencing nonhuman primate novel therapeutics ophthalmic examination oxidation programs recruit serial imaging sex single-cell RNA sequencing sugar therapy development translational study whole genome

项目摘要

PROJECT SUMMARY Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly, but current treatments target advanced stages when interventions may be limited by irreversible cell loss. Soft drusen are the initial and hallmark feature of AMD, but their pathogenesis is unclear and the development of treatments is limited by the lack of good animal models. Unlike most laboratory animals, nonhuman primates (NHPs) possess a true macula and spontaneously develop soft drusen resembling early human AMD. Prior studies of NHP drusen have been observational, cross-sectional, and qualitative, owing to the high costs of maintaining aged animals, limited longitudinal imaging capabilities, and lack of Next-Generation Sequencing (NGS) and bioinformatics support. We recently surveyed a unique colony of geriatric rhesus macaques at the California National Primate Research Center (CNPRC), and found a 30.6% prevalence of drusen. Using high-resolution multimodal in vivo imaging, we precisely measured drusen progression over 2 years, with histological and ultrastructural correlates demonstrating lipid accumulation resembling human soft drusen. Similar to cardiovascular diseases, AMD share epidemiologic risk factors such as high fat diets, susceptibility genes in lipid metabolism, and deposits similar to atherosclerotic plaques with lipoprotein accumulation, lipid oxidation, and complement-based inflammatory responses. Recent pilot studies suggest that high-dose oral atorvastatin can cause drusen regression in some AMD patients, but human studies are limited by the heterogeneity of AMD phenotypes and variability in subject diets and serum lipid concentrations. In this study, we plan to establish a new, unique cohort of aged rhesus macaques with soft drusen, and perform 1) detailed ophthalmic characterization using spectral-domain optical coherence tomography (SD-OCT) to precisely measure retinal layers and track drusen volume, and fundus autofluorescence (FAF) to measure RPE lipofuscin, 2) metabolic profiling to measure fasting plasma metabolites, lipoproteins, and apolipoproteins, and 3) whole-genome sequencing to identify genetic variants in animals with drusen that may be shared with human AMD. Next, we will establish the impact of a “Western-style” high-fat/sugar (HFS) diet and high-dose atorvastatin on drusen progression and RPE health over 2 years, and determine possible correlations with dietary fats and serum lipids. Finally, we will employ NGS-based single-cell RNA-sequencing (scRNA-Seq) to determine the gene expression profile in macular RPE cells with and without soft drusen, exposure to HFS diet, or treatment with high-dose statin, followed by immunohistochemistry of contralateral eyes to evaluate and validate identified gene sets or pathways, as well as complement and other immune pathways. Together, these studies will not only establish a highly-valuable and unique cohort of aged rhesus macaques with soft drusen suitable for translational studies, but also explore the role of dietary lipids, oral statins, RPE gene expression, and immune pathways in this NHP model of early AMD.

项目概要年龄相关性黄斑变性（AMD）是老年人视力丧失的主要原因，但目前的治疗方法针对晚期阶段，此时干预措施可能会受到不可逆细胞损失的限制。 AMD 的标志性特征，但其发病机制尚不清楚，并且治疗方法的开发受到与大多数实验动物不同，非人类灵长类动物（NHP）拥有真正的黄斑。并自发地形成软玻璃膜疣，重新组装早期人类 AMD 的先前研究已被报道。观察性的、横截面的和定性的，由于维持老年动物的高成本而受到限制，有限纵向成像能力，缺乏下一代测序（NGS）和生物信息学支持。我们最近在加州国家灵长类动物研究中心调查了一组独特的老年恒河猴中心 (CNPRC)，使用高分辨率多模态体内成像发现玻璃膜疣的患病率为 30.6%。我们通过组织学和超微结构的相关性精确测量了两年内玻璃膜疣的进展情况与心血管疾病相似，AMD 也具有脂质积累重组人类软玻璃膜疣的作用。流行病学危险因素，如高脂肪饮食、脂质代谢的易感基因以及类似的沉积物动脉粥样硬化斑块伴有脂蛋白积累、脂质氧化和补体炎症最近的初步研究表明，高剂量口服阿托伐他汀可以导致某些人的玻璃疣消退。 AMD 患者，但人类研究受到 AMD 表型异质性和受试者变异性的限制饮食和血清脂质浓度。在这项研究中，我们计划建立一个新的、独特的患有软玻璃膜疣的老年恒河猴群体，并进行 1) 使用谱域光学相干断层扫描 (SD-OCT) 进行详细的眼科表征精确测量视网膜层并跟踪玻璃疣体积，并通过眼底自发荧光 (FAF) 测量 RPE 脂褐质，2) 代谢分析以测量空腹血浆代谢物、脂蛋白和载脂蛋白，以及 3) 全基因组测序，以确定患有玻璃膜疣的动物中可能与人类共有的遗传变异 AMD。接下来，我们将确定“西式”高脂肪/糖 (HFS) 饮食和高剂量阿托伐他汀的影响。 2 年来玻璃疣进展和 RPE 健康状况，并确定与膳食脂肪和最后，我们将采用基于 NGS 的单细胞 RNA 测序 (scRNA-Seq) 来确定有或没有软玻璃膜疣、暴露于 HFS 饮食或治疗的黄斑 RPE 细胞的基因表达谱使用高剂量他汀类药物，然后对对侧眼睛进行免疫组织化学分析以评估和验证已识别的这些研究不会将基因组或途径，以及补体和其他免疫途径结合起来。只建立一个具有软玻璃膜疣的高价值且独特的老年恒河猴群体，适合转化研究，还探索膳食脂质、口服他汀类药物、RPE 基因表达和免疫的作用早期 AMD 的 NHP 模型中的通路。