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

老年性黄斑变性(AMD)是发达国家老年人致盲的主要原因 世界上没有治愈的方法，而且患病率正在迅速上升。因为只有灵长类动物才有斑点，既然没有 AMD模型存在于非人类灵长类动物中，其发病过程需通过深入研究才能阐明 人类的生命。AMD的失明是由视杆细胞和视锥细胞的渐进性和不可逆性死亡引起的 继发于视网膜色素上皮(RPE)的退化，这对他们的健康和 功能。临床影像和组织学已经为我们提供了关于疾病后期的大量信息，但 缺乏了解AMD发病时如何偏离正常衰老的基础知识。使用 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表征健康人的视网膜老化，通过定义 活体RPE-光感受器细胞结构和显微自发荧光随年龄和年龄的变化 波长。这将产生基于AOO细胞的指标的最大体内量化标准数据集 日期，我们将使用这些数据来生成评估新兴市场所需的新的量化分析工具 旨在预防或减缓AMD患者视力丧失的疗法(目标1)。在一项病例对照研究中，我们将比较 正常光感受器和RPE细胞形态计量学对临床早期AMD的定量研究 定义在活体内可以检测到的AMD最早的细胞变化。这项工作将识别细胞 区分正常衰老和早期AMD的变化和表型，以促进早期发病检测。 这些结果将通过与老年人和早期AMD的组织水平变化进行比较来确定 临床影像，特别是脉络膜毛细血管减少和玻璃疣(目标2)。这项研究的结果将导致 AMD的临床诊断和分类系统仅依赖于组织的范式转变- 水平生物标记物或传统的眼底镜临床体征，依赖于体内细胞的严格定量- 基于指标的。这些知识和这些工具将共同奠定开发和 评估限制或预防AMD视力丧失所需的新的预防性疗法。

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.