ANTIOXIDANT SYSTEMS AND AGE RELATED MACULAR DEGENERATION

描述(改编自申请者的摘要)：本研究项目 重点关注老年性黄斑变性(ARMD)可以 由视网膜色素上皮(RPE)的氧化损伤所致 谷胱甘肽(GSH)对ARMD相关视网膜和RPE细胞的保护作用 伴有氧化损伤。先前的研究表明，血液中有一种变化 随着年龄的增长，血浆氧化还原状态变为更氧化的状态，将所有组织置于 年龄相关疾病的风险；似乎也有更氧化的氧化还原 进展期ARMD患者的状态。体外研究表明， 氧化损伤诱导视网膜色素上皮细胞凋亡可能与 线粒体受损。此外，饮食诱导剂可以刺激GSH的增加 合成导致细胞内GSH升高，并伴随增加 防止氧化损伤。在这个项目中，调查人员建议 回答以下将检验他们的假设的问题：(1)如何 氧化还原状态与ARMD有关；(2)参与了什么机制 将GSH氧化还原状态转变为更氧化的状态，从而影响RPE细胞 功能；(3)能否调节人RPE中GSH的合成能力 通过控制GSH合成的限速酶来控制细胞；以及(4)什么 氧化还原调节培养人细胞凋亡的机制 RPE细胞。生化研究，包括高效液相色谱、生存能力研究、 RPE功能、TUNEL法和其他细胞凋亡检测，以及 线粒体功能，将评估人血浆样本，培养 人RPE细胞和实验动物。这些研究应该会增加我们的 对ARMD发病机制的理解，同时直接提出新的建议 治疗策略。

DESCRIPTION (Adapted from the applicant's abstract): This research program focuses on the hypotheses that age-related macular degeneration (ARMD) can result from oxidative injury to the retinal pigment epithelium (RPE) and that glutathione (GSH) may protect the retina and RPE cells from ARMD-associated with oxidative injury. Previous work has shown that there is a shift in blood plasma redox status to a more oxidized state with aging, placing all tissues at risk for age-related diseases; there also appears to be a more oxidized redox state in patients' with more advanced ARMD. In vitro studies suggest that oxidative injury-induced apoptotic cell death in RPE cells may involve mitochondrial damage. Further, dietary inducers can stimulate increased GSH synthesis leading to elevated intracellular GSH, with concomitant increased protection against oxidative injury. In this project, the investigators propose to answer the following questions which will test their hypotheses: (1) how redox status is associated with ARMD; (2) what mechanism is involved in shifting GSH redox status to a more oxidized state that affects RPE cell function; (3) whether one can modulate GSH synthetic capacity in human RPE cells by controlling the rate-limiting enzyme for GSH synthesis; and (4) what mechanisms are involved in the redox regulation of apoptosis in cultured human RPE cells. Biochemical studies, including HPLC, viability studies, measures of RPE function, TUNEL assay and other assays for apoptosis, and assays for mitochondrial function, will evaluate human blood plasma samples, cultured human RPE cells, and experimental animals. These studies should increase our understanding of the pathogenesis of ARMD, while directly suggesting new treatment strategies.