S-glutathionylation chemistry in fibrotic lung remodeling

纤维化肺重塑中的 S-谷胱甘肽化学

• 批准号: 10320789
• 负责人: Yvonne M. W. Janssen-Heininger
• 金额: $ 92.79万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320789
• 关键词: Address; Animals; Antioxidants; Area; Asthma; Attenuated; Biological; Biological Process; Cells; Chemicals; Chemistry; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Client; Clinical; Clinical Trials; Complex; Cysteine; Data; Disease model; Enzymes; Epithelial Cells; Fibrosis; Foundations; Functional disorder; Glutathione; Glutathione S-Transferase P; Goals; Grx1 protein; Immune response; Inflammatory; Knowledge; Laboratories; Lung; Lung diseases; Modification; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Patients; Pharmaceutical Preparations; Play; Process; Protein S; Proteins; Pulmonary Fibrosis; Research; Role; Signal Transduction; Structure of parenchyma of lung; Therapeutic; Thinking; Translations; Work; airway remodeling; allergic airway disease; antioxidant therapy; asthmatic; attenuation; base; clinical practice; combat; fibrotic lung; improved; interstitial; mouse model; novel therapeutics; oxidation; penicillamine-glutathione mixed disulfide; peroxiredoxin; programs; protein function; pulmonary function; response; scaffold; success; uptake

PROJECT SUMMARY It is increasingly recognized that oxidative stress is an important feature in pathophysiology of chronic pulmonary diseases, including asthma, COPD and pulmonary fibrosis. Yet, in spite of some successes in animal studies, clinical trials using antioxidants have been largely ineffective in improving lung function in patients with lung disease, and have not yielded new drugs. Despite these negative clinical trials, it has now become well accepted that oxidants are molecules that carry out important biological functions. My laboratory has discovered that protein S-glutathionylation (PSSG), a redox-based modification of reactive cysteines, plays a critical role in airways remodeling and lung fibrosis. We identified that this process is catalyzed by glutathione S transferase P (GSTP), and reversed by the deglutathionylating enzyme, glutaredoxin-1 (Glrx1) induced de-glutathionylation. The intriguing observations around the GSTP-PSSG-Glrx1 redox axis have formed the foundation for a number of research directions that will be pursued herein. We propose to do so in the setting of interstitial fibrosis and fibrotic remodeling associated with allergic airways disease. The conceptual framework for this R35 over the next seven years consists of five separate goals that include: 1) Identification of redox scaffolds and redox-relay circuits harnessed by scaffolding complexes that encompass peroxiredoxin-4 (Prdx4), GSTP and client proteins that are S-glutathionylated via a redox relay, 2) Avenues to combat protein S-glutathionylation (PSSG) in a target-specific manner by focusing on new avenues for inhibition of GSTP, 3) Understanding mechanisms of cellular uptake/secretion of Glrx1, approaches to modify stability of and deliver Glrx1 to specific cellular compartments to enhance its de-glutathionylating function, 4) Address whether altered inflammatory/immune responses contribute to the diminished fibrogenic response upon attenuation of S-glutathionylation, and 5) Elucidate targets for PSSG in epithelial cells from asthmatics and lung tissues from patients with IPF and address whether strategies to attenuate PSSG diminish pro-inflammatory/pro-remodeling responses in epithelial cells from patients with asthma: The project areas identified have the strong potential to advance our knowledge of how biological oxidations, specifically PSSG, are controlled, with the goal to identify strategies to intervene with protein cysteine oxidations in a target- or compartment-specific manner. The anticipated outcomes will be molecules that are therapeutically applicable and overcome the lack of efficacy observed with the use of non- specific generic antioxidants in the treatment of pulmonary diseases. This research program has the potential to be paradigm-shifting as it changes conventional thinking of how oxidants contribute to lung disease (oxidative stress) toward a paradigm wherein oxidants transduce signals via highly scaffolded “electrical circuits”.

项目摘要 人们越来越认识到氧化应激是慢性肺病理生理学的重要特征 疾病，包括哮喘，COPD和肺纤维化。然而，尽管动物研究取得了一些成功，但 使用抗氧化剂的临床试验在改善肺患者的肺功能方面基本上无效 疾病，尚未产生新药。尽管进行了负面的临床试验，但现在已被广泛接受 氧化剂是执行重要生物学功能的分子。我的实验室发现 基于氧化还原的反应性半胱氨酸的蛋白质S-谷胱甘肽化（PSSG）在 气道重塑和肺纤维化。我们确定该过程是由谷胱甘肽的转移酶p催化的 （GSTP），并由脱发二酰基化酶，谷胱甘肽-1（GLRX1）诱导的De-lutathionylation逆转。 GSTP-PSSG-GLX1氧化还原轴周围的有趣观察结果为一个数字构成了基础 在这里将追求的研究方向。我们建议在间质纤维化和 与过敏性气道疾病相关的纤维化重塑。此R35的概念框架 接下来的七年包括五个单独的目标，其中包括：1）鉴定氧化还原支架和氧化还原 - 雷德 由脚手架复合物（PRDX4），GSTP和客户蛋白所利用的电路 通过氧化还原继电器对S-谷二酰二离子化，2）在A中对抗蛋白S-谷酰二酰化（PSSG）的途径 通过关注抑制GSTP的新途径，特定于目标的方式，3）理解机制 GLRX1的细胞摄取/分泌，可修饰GLRX1的稳定性和传递特定细胞的稳定性方法 隔间以增强其去谷二烯基化功能，4）解决炎症/免疫的改变 反应会导致纤维化反应减少，而S-glutathiyylation衰减，而5） 阐明来自IPF患者哮喘和肺组织上皮细胞中PSSG的靶标 衰减PSSG的策略是否会减少上皮细胞中的促炎/促进反应 哮喘患者：所确定的项目领域具有促进我们对我们的了解的强大潜力 如何控制生物氧化，特别是PSSG，其目标是确定干预的策略 蛋白质半胱氨酸的氧化以特异性或区室特异性方式。预期的结果将是 热适用的分子并克服了缺乏使用非效率的分子 特定的普通抗氧化剂治疗肺部疾病。该研究计划有可能 范式转移，因为它改变了氧化剂如何对肺部疾病的贡献（氧化）的常规思考 压力）朝向范式通过高度脚手架的“电路”传递信号的范式。