S-glutathionylation chemistry in fibrotic lung remodeling

项目总结 越来越多的人认识到氧化应激是慢性肺病病理生理学的重要特征。 疾病，包括哮喘、慢性阻塞性肺病和肺纤维化。然而，尽管在动物研究中取得了一些成功， 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无效。 疾病，并且还没有产生新的药物。尽管有这些负面的临床试验，它现在已经被广泛接受。 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谷胱甘肽基化是一种基于氧化还原的反应性半胱氨酸的修饰，在 气道重塑和肺纤维化。我们确定这一过程是由谷胱甘肽S转移酶P催化的。 (GSTP)，并被谷胱甘肽还原酶逆转，谷氧还蛋白-1(Glrx1)诱导去谷胱甘肽。 围绕GSTP-PSSG-Glrx1氧化还原轴的有趣观察为以下几个 将在这里追求的研究方向。我们建议在间质纤维化的情况下这样做 与过敏性呼吸道疾病相关的纤维化重塑。这款R35的概念框架 未来七年包括五个不同的目标，包括：1)确定氧化还原支架和氧化还原接力 由包含过氧化还蛋白-4(Prdx4)、GSTP和客户蛋白的支架复合体控制的回路 这些都是通过氧化还原继电器使S谷胱甘肽基化，2)对抗蛋白质S谷胱甘肽基化的途径 通过关注抑制GSTP的新途径，以靶向特异的方式，3)了解GSTP的机制 细胞摄取/分泌Glrx1，改变Glrx1的稳定性并将Glrx1运送到特定细胞的方法 增强其去谷胱甘肽功能的隔室，4)解决是否改变炎症/免疫 反应有助于减弱S-谷胱甘肽基化后的纤维化反应，以及5) 哮喘患者上皮细胞和IPF患者肺组织中PSSG靶点的阐明及地址 抑制PSSG的策略是否会减少上皮细胞的促炎/促重塑反应 来自哮喘患者：确定的项目领域具有极大的潜力来促进我们对 如何控制生物氧化，特别是PSSG，目的是确定干预策略 蛋白质半胱氨酸以靶标或隔室特定的方式氧化。预期结果将是 可用于治疗的分子，并克服了使用非药物时观察到的疗效不足 肺部疾病治疗中的特殊通用抗氧化剂。这项研究计划有可能 转变范式，因为它改变了关于氧化剂如何导致肺部疾病的传统思维(氧化 应激)向氧化剂通过高度支架化的“电路”传递信号的模式转变。

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”.