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”.

项目概要 人们越来越认识到氧化应激是慢性肺疾病病理生理学的一个重要特征。 疾病，包括哮喘、慢性阻塞性肺病和肺纤维化。然而，尽管动物研究取得了一些成功， 使用抗氧化剂的临床试验在改善肺病患者的肺功能方面基本上无效 疾病，尚未产生新药。尽管有这些负面的临床试验，但它现在已被广泛接受 氧化剂是执行重要生物功能的分子。我的实验室发现 蛋白质 S-谷胱甘肽 (PSSG) 是一种基于氧化还原的反应性半胱氨酸修饰，在 气道重塑和肺纤维化。我们确定该过程是由谷胱甘肽 S 转移酶 P 催化的 (GSTP)，并被去谷胱甘肽酶、谷氧还蛋白-1 (Glrx1) 诱导的去谷胱甘肽逆转。 围绕 GSTP-PSSG-Glrx1 氧化还原轴的有趣观察结果为许多研究奠定了基础 本文将要追求的研究方向。我们建议在间质纤维化的情况下这样做 与过敏性气道疾病相关的纤维化重塑。 R35 的概念框架 未来七年由五个单独的目标组成，其中包括：1）氧化还原支架和氧化还原继电器的识别 由包含 peroxiredoxin-4 (Prdx4)、GSTP 和客户蛋白的支架复合物利用的电路 通过氧化还原继电器进行 S-谷胱甘肽化，2) 对抗蛋白质 S-谷胱甘肽化 (PSSG) 的途径 通过关注抑制 GSTP 的新途径，以特定目标的方式，3) 了解 Glrx1 的细胞摄取/分泌，修改 Glrx1 稳定性并将 Glrx1 递送至特定细胞的方法 隔室以增强其去谷胱甘肽功能，4）解决炎症/免疫是否改变 S-谷胱甘肽减弱后的反应有助于减少纤维形成反应，5) 阐明哮喘患者上皮细胞和 IPF 患者肺组织中 PSSG 的靶点并解决 减弱 PSSG 的策略是否会减少上皮细胞的促炎症/促重塑反应 来自哮喘患者：所确定的项目领域具有巨大的潜力，可以提高我们对哮喘的认识 如何控制生物氧化，特别是 PSSG，目的是确定干预策略 以靶点或区室特异性方式进行蛋白质半胱氨酸氧化。预期结果将是 分子在治疗上适用并克服了使用非药物观察到的功效缺乏 治疗肺部疾病的特定通用抗氧化剂。该研究计划有潜力 是范式转变，因为它改变了氧化剂如何导致肺部疾病的传统思维（氧化 压力）转向氧化剂通过高度支架的“电路”转导信号的范例。