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

总结 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，导致与年龄相关的眼部疾病，包括白内障。蛋白 谷胱甘肽化，即谷胱甘肽和蛋白质硫醇之间混合二硫化物的可逆形成，是 氧化应激反应中的主要氧化蛋白质修饰。谷氧还蛋白（Grx）系统修复 蛋白质巯基化并维持细胞氧化还原平衡。Grx系统有两种同种型，细胞溶质Grx 1（也 称为巯基转移酶）和线粒体Grx 2。本提案的目的是研究Grx系统如何 功能障碍可能影响透镜氧化还原信号传导及其透明度。我们假设Grx 1/Grx 2加倍 缺失可通过抑制核转录因子的表达而增加透镜对紫外线（UV）辐射和老化的敏感性。 红细胞2因子相关因子2（Nrf 2）依赖性抗氧化反应。我们还建议GRX- 活化化合物可保护透镜免于UV诱导的白内障形成。来证明我们 假设，提出了以下具体目标：1）确定Grx系统在保护 使用Grx 1/Grx 2 DKO小鼠作为模型，观察透镜的UV辐射和老化。2)为了检查串扰 Grx系统和Nrf 2-抗氧化途径之间的联系。3)为了测试Grx激活化合物是否能保护 透镜从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，并可能导致开发Grx激活化合物作为潜在的治疗药物， 白内障和其他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.