Distinguishing normal aging from age-related macular degeneration at the level of single cells int eh living human eye

在活体人眼的单细胞水平上区分正常衰老和年龄相关性黄斑变性

• 批准号: 9973645
• 负责人: Ethan A Rossi
• 金额: $ 52.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973645
• 关键词: Age; Age related macular degeneration; Aging; Area; Atrophic; Biological Markers; Blindness; Bruch' s basal membrane structure; Case-Control Studies; Cells; Cessation of life; Choroid; Classification; Clinical; Clinical Research; Complex; Conflict (Psychology); Cross-Sectional Studies; Cytoplasmic Granules; Data; Data Set; Detection; Development; Diagnostic Procedure; Disease; Drusen; Elderly; Evaluation; Eye; Foundations; Genetic; Goals; Health; Histology; Histopathology; Human; Image; Image Analysis; Individual; Knowledge; Lead; Lipofuscin; Machine Learning; Maps; Melanins; Methods; Microscopic; Modeling; Monitor; Ophthalmoscopy; Optical Coherence Tomography; Optics; Perfusion; Phenotype; Photoreceptors; Prevalence; Preventive therapy; Preventive treatment; Primate Diseases; Primates; Public Health; Retina; Retinal Cone; Retinal Degeneration; Retinal Photoreceptors; Risk; Secondary to; Spatial Distribution; Structure; Structure of retinal pigment epithelium; System; Techniques; Technology; Testing; Therapy Evaluation; Time; Tissues; Variant; Vertebrate Photoreceptors; Vision; Work; adaptive optics; age related; aging population; base; clinical Diagnosis; clinical decision-making; clinical imaging; cohort; early onset; fluorophore; healthy aging; imaging modality; imaging platform; improved; in vivo; macula; morphometry; multimodality; neurovascular unit; nonhuman primate; normal aging; prevent; restorative treatment; retinal imaging; retinal rods; therapy design; tool

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world; no cure exists and prevalence is rising rapidly. Because only primates have a macula and since no model of AMD exists in non-human primates, the disease course can only be elucidated through in-depth study of humans. Blindness in AMD is caused by progressive and irreversible death of rod and cone photoreceptors secondary to degeneration of the retinal pigment epithelium (RPE) that is essential for their health and function. Clinical imaging and histology have informed us greatly about the later stages of disease but fundamental knowledge to understand how AMD diverges from normal aging at onset is lacking. With advanced adaptive optics ophthalmoscopy (AOO) imaging methods, combined with clinical imaging and visual function testing, we will characterize healthy human retinal aging in cross-sectional study, by defining the in vivo RPE-photoreceptor cellular organization and microscopic autofluorescence variation with age and wavelength. This will produce the largest quantitative in vivo normative dataset of AOO cell-based metrics to date and we will use this data to generate new quantitative analysis tools needed to evaluate emerging therapies designed to prevent or slow vision loss in AMD (Aim 1). In a case-control study, we will then compare normal photoreceptor topography and RPE cell morphometry to clinically defined early AMD to quantitatively define the earliest cellular changes in AMD that can be detected in vivo. This work will identify the cellular alterations and phenotypes that differentiate normal aging from early AMD to facilitate early onset detection. These results will be contextualized by comparison to tissue-level alterations seen with aging and early AMD in clinical imaging, specifically choriocapillaris decline and drusen (Aim 2). The results of this study will result in a paradigm shift from the use of clinical diagnosis and classification systems for AMD that rely solely on tissue- level biomarkers or traditional funduscopic clinical signs to those that rely on rigorous quantitative in vivo cell- based metrics. Together, this knowledge and these tools will lay the foundation needed to develop and evaluate new preventative therapies that are needed to limit or prevent vision loss in AMD.

视网膜相关性黄斑变性（AMD）是发达国家中老年人失明的主要原因。 世界上没有治愈的方法，流行率正在迅速上升。因为只有灵长类动物才有斑疹，而且没有 AMD模型存在于非人灵长类动物中，只有通过深入研究才能阐明疾病过程 人类AMD致盲是由于视杆细胞和视锥细胞的进行性和不可逆的死亡 继发于视网膜色素上皮（RPE）的变性，这对他们的健康至关重要， 功能临床影像学和组织学为我们提供了关于疾病后期的大量信息， 缺乏了解AMD如何在发病时偏离正常衰老的基本知识。与 先进的自适应光学检眼镜（AOO）成像方法，结合临床成像和视觉 功能测试，我们将在横断面研究中描述健康人视网膜老化的特征， 体内RPE感光细胞组织和显微自发荧光随年龄的变化， 波长这将产生基于AOO细胞的指标的最大定量体内标准数据集， 日期，我们将使用这些数据来生成新的定量分析工具，以评估新兴的 旨在预防或减缓AMD视力丧失的治疗（目标1）。在病例对照研究中，我们将比较 正常光感受器地形图和RPE细胞形态计量学与临床定义的早期AMD定量比较， 定义了AMD中可以在体内检测到的最早的细胞变化。这项工作将确定细胞 这些改变和表型可区分正常老化和早期AMD，以促进早期发病检测。 这些结果将通过与老年人和早期AMD中观察到的组织水平变化进行比较来进行背景分析。 临床影像学，特别是脉络膜毛细血管下降和玻璃疣（目的2）。这项研究的结果将导致一个 从使用仅依赖于组织的AMD临床诊断和分类系统的范式转变， 水平的生物标志物或传统的眼底镜临床体征，以那些依赖于严格的定量体内细胞， 基于Metrics。这些知识和这些工具将共同奠定发展和 评估限制或预防AMD视力丧失所需的新的预防性疗法。