PROTEOMIC ANALYSIS OF AGE-RELATED MACULAR DEGENERATION

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是西方世界老年人失明的主要原因。到目前为止，几种“破坏性”的治疗方式已经被尝试，以改善黄斑变性患者的中央视力无效。开发有效治疗的失败源于我们对AMD发病机制的细胞机制的认识不足。一些流行病学研究表明，衰老是AMD的主要危险因素。实验数据表明，细胞蛋白的糖基化、磷酸化或氧化等翻译后修饰可能导致与年龄相关的视网膜细胞损失。然而，与年龄相关的视网膜细胞丢失和导致AMD的宏观结构改变的确切机制尚未确定。识别这些发病途径将有助于我们制定合理的策略来阻止导致AMD的细胞事件。本实验旨在确定(1)年轻（<50岁）正常供者，(2)无视网膜病变的正常老年（65岁以上）供者，(3)年龄相关性黄斑病变（ARM）的老年供者，(4)老年AMD供者黄斑和周围的RPE、绒毛膜毛细血管和光感受器细胞的原位蛋白表达差异。这些蛋白质组图的比较将揭示每种细胞类型的蛋白质表达的地形和年龄相关的变化。这种蛋白质组图也将有助于检测ARM和AMD中差异表达的蛋白质。使用生物信息学技术，可能的病理事件和相关途径将被确定。拟议的研究还将产生每个组织的地形和年龄相关的特定蛋白质组图，可用于该领域的未来研究。这一建议的结果无疑将提高我们对AMD中细胞死亡的确切机制的理解，并有助于开发针对已确定的病理途径的更具体的治疗技术。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population in the Western world. So far, several "destructive" treatment modalities have been tried in vain to improve the central vision in patients with AMD. The failure of developing effective treatment stems from the inadequacy of our knowledge of cellular mechanisms in AMD pathogenesis. Several epidemiological studies indicate aging as the predominant risk factor for AMD. Experimental data suggest that post-translational modifications of cellular proteins by glycation, phosphorylation or oxidation may be responsible for age related retinal cell loss. However, the exact mechanisms involved in age-related retinal cell loss and macrostructural alterations leading to AMD have not yet been identified. Identification of these pathogenetic pathways will help us to develop rational strategies to block the cellular events leading to AMD. Proposed experiments aim to identify the differential in situ protein expressions of RPE, choriocapillaris and photoreceptor cells in the macula and periphery of the (1) young (<50) normal donors, (2) normal old (>65) donors without any retinal pathology, (3) old donors with age-related maculopathy (ARM), and (4) old donors with AMD. Comparison of these proteome maps will reveal the topographical and age-related variations in protein expression of each cell type. Such proteome maps will also be useful in detecting the differentially expressed proteins in ARM and in AMD. Using bioinformatic techniques, possible pathological events and related pathways will be identified. Proposed studies will also yield topographical and age-correlated specific proteome maps of each tissue which can be used for future research in the field. Results of this proposal will undoubtedly improve our understanding of the precise mechanisms of cell death in AMD and facilitate efforts to develop more specific treatment techniques aimed at identified pathological pathways.