Antioxidant Systems and Age-related Macular Degeneration

描述（由申请人提供）：最近的AREDS数据强烈支持氧化应激在AMD发病机制中的作用，该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。该更新申请的目的是定义视网膜氧化应激的遗传和生化标志物，以便在发生显著视力丧失之前，可以识别处于AMD的较高风险或早期阶段的人，并通过补充其抗氧化防御进行治疗。我们的AREDS辅助研究显示，血浆巯基/二硫化物氧化还原状态在未补充抗氧化剂的AMD患者中随着时间的推移而变得氧化，但在补充抗氧化剂的患者中则不然。此外，我们发现血浆半胱氨酸和谷胱甘肽池的氧化与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，范德比尔特的新合作者最近的结果表明，特定的线粒体DNA单倍型可能与AMD风险增加有关。综上所述，数据强烈表明AMD的病因和进展涉及遗传/环境相互作用，氧化应激是导致年龄相关组织变性、炎症和遗传易感性机制的常见机制。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志物可用于识别AMD风险增加的人，并预测抗氧化剂补充临床治疗的结果。我们提出三个具体目标来回答以下问题。(1)氧化应激和促炎细胞因子的血浆标志物与衰老和AMD相关吗？(2)是否有特定的线粒体DNA多态性与氧化应激增加的标志物以及AMD表型相关？(3)饮食干预能否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？这项综合性的基础机制、转化和临床研究项目的结果将促进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.