The Effects of PP2A on TNF Signaling and Smoke-Induced Lung Injury

描述（由申请人提供）：迄今为止，没有有效的治疗方法可以抵消香烟烟雾在肺部的破坏性影响。事实上，慢性阻塞性肺疾病（COPD）的年龄调整死亡率在过去30年中上升了71%。为了改善这一趋势，需要制定更有效的治疗潜在疾病机制的战略。信号激酶的异常激活在本病发生的病理生理反应中发挥核心作用。这些激酶的活性受到细胞内磷酸酶的严格调控；然而，我们对这些蛋白在COPD发病机制中的作用的了解非常有限。PP2A是存在于所有真核细胞中的主要丝氨酸苏氨酸蛋白磷酸酶。在其众多功能中，它可以使JNK和c-Jun去磷酸化和失活；因此，它是肺中TNF信号通路的主要调节因子。我们最近发表了一项研究，超氧化物歧化酶-1 (SOD1)，一种肺部抗氧化剂，可以防止香烟引起的炎症和肺气肿的形成。我们实验室的进一步研究表明，SOD1和谷胱甘肽过氧化物酶-1 （GPX1）增加了这些转基因小鼠肺部PP2A的活性，降低了AP-1的活性。这表明抗氧化剂通过其对PP2A的作用，可以改变这种疾病中关键信号通路的激活状态。我们假设抗氧化剂通过增强PP2A活性从而降低肺中AP-1信号传导来防止烟雾引起的肺损伤。这一假设基于我们实验室前期研究的三个重要发现：1)SOD1/GPX1增加肺部PP2A活性，但不改变表达或蛋白水平；2)小鼠肺部PP2A活性的增加与肺部AP-1核结合减少有关；3)JNK抑制减少香烟引起的小鼠肺部炎症。本提案将探讨抗氧化剂如何改变PP2A活性（目的1）。此外，它将确定PP2A活性增加是否对抗TNF信号和烟雾诱导的肺损伤（Aim 2）。最后，它将解决PP2A活性或分布是否改变肺气肿患者肺中的TNF信号（目的3）。我们相信，从这些研究中获得的见解将为治疗这种疾病提供更有针对性的策略，并具有在未来为公共卫生做出重大贡献的强大潜力。此外，我们的发现不仅对慢性阻塞性肺病，而且对TNF信号和炎症起核心作用的其他疾病也具有重要意义。

DESCRIPTION (provided by applicant): To date, there are no effective therapies that can counteract the damaging effects of cigarette smoke exposure in the lung. In fact, the age-adjusted mortality for chronic obstructive pulmonary disease (COPD) has risen 71% over the past thirty years. To improve this trend more effective strategies of treating the underlying disease mechanisms need to be developed. Aberrant activation of signaling kinases exerts a central role on the pathophysiologic responses that occur in this disease. The activity of these kinases is tightly regulated by intracellular phosphatases; however, our knowledge of the role of these proteins in the pathogenesis of COPD is extremely limited. PP2A is the major serine threonine protein phosphatase present in all eukaryotic cells. Among its many functions, it dephosphorylates and inactivates both JNK and c-Jun; thus, it is a major regulator of the TNF signaling pathway in the lung. We have recently published that superoxide dismutase-1 (SOD1), a lung antioxidant, prevents cigarette smoke-induced inflammation and emphysema formation in mice. Further studies in our laboratory demonstrated that SOD1 and glutathione peroxidase-1 (GPX1) increase PP2A activity and decrease AP-1 activation in the lungs of these transgenic mice. This indicates that antioxidants, via their effects on PP2A, can alter the activation state of this pivotal signaling pathway in this disease. We hypothesize that antioxidants protect against smoke-induced lung injury by enhancing PP2A activity thereby decreasing AP-1 signaling in the lung. This hypothesis is based on three important findings from prior studies in our laboratory: 1) SOD1/GPX1 increases PP2A activity in the lung without altering expression or protein levels, 2) Increases in PP2A activity in the lungs of mice is associated with reduced AP-1 nuclear binding in the lung and 3) JNK inhibition decreases cigarette smoke-induced lung inflammation in mice. This proposal will address how antioxidants alter PP2A activity (Aim 1). In addition, it will determine whether increasing PP2A activity counters TNF signaling and smoke-induced lung injury in this disease (Aim 2). Finally, it will address if PP2A activity or distribution alters TNF signaling in the lungs of emphysema patients (Aim 3). We believe that the insights gained from these studies will provide more targeted strategies of treating this disease and have the strong potential to make a significant contribution to public health in the future. Moreover, our findings will have important implications not only for COPD but also for other diseases where TNF signaling and inflammation play a central role. PUBLIC HEALTH RELEVANCE: While a significant body of research has elucidated the role that protein kinases exert in COPD, much less is know about the effects of protein phosphatases. This proposal will advance public health by determining how PP2A, the primary eukaryotic serine/threonine phosphatase, alters the injurious responses to cigarette smoke exposure in the lung.