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

晶状体中谷氧还蛋白 (Grx) 系统的机理见解和治疗潜力

基本信息

批准号：
10592813
负责人：
Hongli Wu
金额：
$ 22.84万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592813
关键词：
Adenosine Triphosphate Affect Age Aging Antioxidants Attention Binding Blindness Cataract Collaborations Complex Crystallins Data Development Disulfides Dose Drug Targeting Elderly Enzymes Epithelial Cells Equilibrium Euthanasia Exposure to Eye diseases Family Female Functional disorder GATA1 gene Genes Genetic Transcription Glutathione Glutathione Disulfide Grx1 protein Heme Heterocyclic Amines Histology Homeostasis Hydrogen Peroxide Individual Isoenzymes Knock-out Knockout Mice Mammalian Cell Measures Microscope Mitochondria Modeling Monitor Morphology Mothers Mus NQO1 gene Organ Culture Techniques Oxidation-Reduction Oxidative Stress Oxygenases Pathway interactions Persons Play Post-Translational Protein Processing Predisposition Prevalence Prevention Protein Isoforms Proteins Risk Factors Role Series Signal Transduction Sulfhydryl Compounds Superoxide Dismutase Surface Plasmon Resonance System TXN gene Techniques Testing Texas Therapeutic Therapeutic Agents Time Tissues UV Radiation Exposure UV induced Ultraviolet Rays Western Blotting Wild Type Mouse age related aging population antioxidant enzyme enzyme activity glutaredoxin glutaredoxin 2 glutathione peroxidase high risk innovation insight lens lens transparency male meter mouse model novel therapeutics nuclear factor-erythroid 2 oxidation oxidative damage pharmacologic preservation protective effect protein aggregation repair enzyme repaired response success thioltransferase treatment group trend

项目摘要

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.

概括老年人中最常见的视力丧失原因是白内障。众所周知氧化应激会引起细胞和组织损伤，导致年龄相关的眼部疾病，包括白内障。蛋白质谷胱甘肽化是谷胱甘肽和蛋白硫醇之间混合二硫化物的可逆形成，是一种对氧化应激的响应氧化蛋白的主要修饰。谷糖（GRX）系统维修蛋白质硫醇并保持细胞氧化还原平衡。 GRX系统具有两个同工型，胞质GRX1（也是称为硫代转移酶）和线粒体GRX2。该建议的目的是研究GRX系统如何功能障碍可能会影响镜头氧化还原信号及其透明度。我们假设Grx1/grx2 double 缺失可能会增加透镜对紫外线（UV）辐射的敏感性和通过抑制核的衰老因子红细胞2相关因子2（NRF2）依赖性抗氧化剂反应。我们还建议GRX- 激活化合物可以保护透镜免受紫外线诱导的白内障形成。证明我们的假设，提出了以下具体目标：1）确定GRX系统在保护该系统中的作用使用GRX1/GRX2 DKO小鼠从UV辐射和老化的镜头作为模型。 2）检查串扰在GRX系统和NRF2抗氧化途径之间。 3）测试GRX激活化合物是否可以保护紫外线诱导的白内障形成的镜头。这些目标的成功完成将引入GRX系统作为药物靶标，可能导致GRX激活化合物的发展作为潜在的治疗方法白内障和其他氧化应激相关的眼部疾病。