Mechanistic Insights and Therapeutic Potential of the Glutaredoxin (Grx) System in the Lens

摘要 老年人视力丧失的最常见原因是白内障。众所周知，氧化应激会导致 细胞和组织损伤，导致年龄相关的眼部疾病，包括白内障。蛋白 谷胱甘肽基化是谷胱甘肽和蛋白质硫醇之间混合二硫键的可逆形成，是 主要的氧化蛋白质修饰是对氧化应激的反应。谷氧还蛋白(GRX)系统修复 蛋白质硫醇，维持细胞氧化还原平衡。GRX系统有两种异构体，胞质Grx1(也 称为硫醇转移酶)和线粒体Grx2。这项建议的目的是研究GRX系统如何 功能障碍可能会影响晶状体氧化还原信号及其透明度。我们假设Grx1/Grx2加倍 缺失可能通过抑制细胞核而增加晶状体对紫外线(UV)辐射和衰老的敏感性 因子红系相关因子2(NRF2)依赖的抗氧化反应。我们还建议GRX- 活性化合物可以保护晶状体免受紫外线诱导的白内障的形成。为了证明我们的 假设，提出了以下具体目标：1)确定GRX系统在保护 以Grx1/Grx2 DKO小鼠为模型，观察晶状体抗紫外线辐射和老化的作用。2)检查串扰 在GRX系统和Nrf2-抗氧化剂途径之间。3)测试GRX激活剂是否能保护 晶状体来自紫外线诱导的白内障形成。成功完成这些目标将引入GRX系统 作为药物靶点，并可能导致GRX激活化合物的开发，作为一种潜在的治疗 白内障和其他与氧化应激相关的眼病。

Summary The most common cause of vision loss among the elderly is cataract. Oxidative stress is well known to cause cellular and tissue damage, resulting in age-associated ocular diseases, including cataract. Protein glutathionylation, the reversible formation of a mixed-disulfide between glutathione and protein thiols, is one of the major oxidative protein modifications in response to oxidative stress. The glutaredoxin (Grx) system repairs protein thiols and maintains cellular redox balance. The Grx system has two isoforms, the cytosolic Grx1 (also known as thioltransferase) and the mitochondrial Grx2. The purpose of this proposal is to study how Grx system dysfunction may affect the lens redox signaling and its transparency. We hypothesize that Grx1/Grx2 double deletion may increase the lens susceptibility to ultraviolet (UV) radiation and aging by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. We also propose that Grx- activating compounds could protect the lens from UV-induced cataract formation. To prove our hypotheses, the following Specific Aims are proposed: 1) To identify the role of the Grx system in protecting the lens from UV radiation and aging using the Grx1/Grx2 DKO mouse as a model. 2) To examine the crosstalk between the Grx system and the Nrf2-antioxidant pathway. 3) To test if Grx activating compounds could protect the lens from UV-induced cataract formation. Successful completion of these aims will introduce the Grx system as a drug target and may lead to the development of Grx-activating compounds as a potential therapeutic for cataract and other oxidative stress-associated eye diseases.