Antioxidant Systems and Age-related Macular Degeneration

描述(申请人提供)：最近的AREDS数据显示，补充抗氧化剂和锌可以显著降低疾病进展的风险，这有力地支持了氧化应激在AMD发病机制中的作用。这一更新应用的目标是定义视网膜氧化应激的遗传和生化标记物，以便在发生严重视力丧失之前，可以识别出高风险或处于AMD早期阶段的人，并补充他们的抗氧化防御。我们的AREDS辅助研究显示，在没有补充抗氧化剂的AMD患者中，血浆硫醇/二硫代氧化还原状态随着时间的推移而被氧化，但在那些服用抗氧化剂的患者中没有。此外，我们还发现血浆半胱氨酸库和谷胱甘肽库的氧化与AMD的危险因素有关，如衰老和吸烟。我们的初步数据表明，血浆促凋亡和促炎细胞因子，如可溶性Fas配体，与血浆氧化还原状态和AMD相关。此外，最近与Vanderbilt的新合作者进行的研究结果表明，特定的线粒体DNA单倍型可能与AMD风险增加有关。综上所述，这些数据有力地表明，AMD的病因和进展涉及遗传/环境相互作用，而氧化应激是导致年龄相关组织退化、炎症和遗传易感性的常见机制。我们对这一应用的中心假设是，氧化应激的遗传和血浆生化标记物可以用来识别AMD风险增加的人，并预测补充抗氧化剂的临床治疗结果。我们提出了三个具体目标来回答以下问题。(1)血浆氧化应激标志物和促炎细胞因子是否与年龄和AMD有关？(2)线粒体DNA多态性是否与氧化应激标志物和AMD表型有关？(3)饮食干预是否可以改变不同遗传背景的AMD患者的氧化应激和促炎细胞因子的血浆标志物。这个基础机制、翻译和临床研究的综合项目的结果将有助于AMD的早期诊断和治疗，并直接提出新的治疗策略，重点是加强视网膜和RPE的抗氧化能力。

DESCRIPTION (provided by applicant): A role for oxidative stress in the pathogenesis of AMD is strongly supported by the recent AREDS data showing that supplemental antioxidants and zinc can significantly reduce the risk of disease progression. The goal of this renewal application is to define genetic and biochemical markers of retinal oxidative stress so that people at higher risk or at earlier stages of AMD can be identified and treated with supplementation of their antioxidant defense before the development of significant vision loss. Our AREDS ancillary study showed that plasma thiol/disulfide redox state became oxidized with time in AMD patients without antioxidant supplementation, but not in those with antioxidants. In addition, we found that oxidation of plasma cysteine and glutathione pools are associated with risk factors of AMD, such as aging and smoking. Our preliminary data indicate that plasma pro-apoptotic and pro-inflammatory cytokines, such as soluble Fas ligand, are correlated with plasma redox status and AMD. Furthermore, recent results, performed with new collaborators at Vanderbilt, indicate that specific mitochondrial DNA haplotypes may be associated with an increased risk of AMD. Taken together, the data strongly suggest that the etiology and progression of AMD involves genetic/environmental interaction, and oxidative stress is a common mechanism contributing to age-related tissue degeneration, inflammation and mechanisms of genetic predisposition. Our central hypothesis for this application is that genetic and plasma biochemical markers of oxidative stress can be used to identify people with increased risk of AMD and to predict the outcome of clinical treatment with antioxidant supplementation. We propose three specific aims to answer the following questions. (1) Are plasma markers of oxidative stress and proinflammatory cytokines associated with aging and AMD? (2) Are there specific mitochondrial DNA polymorphisms that are associated with markers of increased oxidative stress as well as the AMD phenotype? (3) Can dietary interventions modify plasma markers of oxidative stress and proinflammatory cytokines in AMD patients with different genetic backgrounds. Results from this comprehensive project of basic mechanistic, translational and clinical studies will facilitate the early diagnosis and treatment of AMD and directly suggest new therapeutic strategies that focus on strengthening the antioxidant capacity of the retina and the RPE.