The Role of Peroxiredoxin 4 in Idiopathic Pulmonary Fibrosis

项目摘要 在美国，每年有4万人被诊断出患有特发性肺纤维化(IPF)。特发性肺纤维化的诊断 本质上是死刑，因为患者在确诊后只有2-3年的存活时间。的最新进展 对IPF的了解导致了两种治疗IPF的新药的开发，9tedanib和吡非尼酮， 然而，两种药物都没有显着延长确诊后的寿命。我们的研究一直集中在 了解氧化应激在IPF发生和发展中的作用。细胞氧化应激由来已久 与IPF有关，然而，过去使用抗氧化剂化合物的治疗被证明无效。我们相信 这些过去的疗法之所以失败，是因为对涉及到的机制缺乏了解 亚细胞水平的氧化应激。通过我们的研究，我们将深入了解潜在的机制 和内质网(ER)中与细胞氧化应激相关的信号。急诊室是一个明确的 大多数蛋白质是正确折叠的，内质网氧化还原状态的任何变化都会产生很大的影响 许多蛋白质的氧化还原状态。获得的新知识将使有针对性的发展成为可能 抗氧化剂治疗特发性肺纤维化。我们推测，通过减轻肺上皮细胞的氧化应激，我们 可以阻止上皮细胞死亡，从而阻止和逆转IPF的进展。为了检验我们的假设，我们将 用促凋亡信号蛋白Fas配体(FasL)处理肺上皮细胞，并测量一个关键分子的水平 内质网中的细胞氧化剂，过氧化氢(H2O2)。然后我们将评估调节活动的效果 表达最高的ER-H_2O_2清除剂--过氧化还蛋白4(Prdx4)对ER氧化还原动态平衡和细胞的影响 死亡。为了进一步验证我们的发现，我们将使用肺纤维化的小鼠模型进行研究 我们可以诱导Prdx4的消融。使用这个模型，我们将展示减少细胞氢的效果。 过氧化水平对肺纤维化发生发展的影响。最后，我们将验证我们的发现 通过进行一组类似的实验来获取过氧化氢水平和 人IPF肺组织中的蛋白质氧化状态。在我们完成研究后，我们会有更好的把握 关于氧化应激在内质网中的作用，这可以用来创建更有针对性的抗氧化疗法 特发性肺纤维化的治疗。

Project Summary In the US 40,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) every year. Diagnosis of IPF is essentially a death sentence since patient survival is only 2-3 years after diagnosis. Recent advances in understanding IPF have led to the development of two new drugs to treat IPF, nintedanib and pirfenidone, however neither drug significantly increases life span after diagnosis. Our research has been focused on understanding the role or oxidative stress in the onset and progression of IPF. Cellular oxidative stress has long been linked with IPF, however past treatments with antioxidant compounds have proven ineffective. We believe that these past therapies have failed because there is a lack of understanding of the mechanisms involved in oxidative stress at a subcellular level. Through our research, we will gain insight into the underlying mechanisms and signals associated with cellular oxidative stress in the endoplasmic reticulum (ER). The ER is where a clear majority of proteins are properly folded, and any changes in the redox status of the ER will have a large impact on the redox state of many proteins. The new knowledge gained will allow for the development of targeted antioxidant therapies to treat IPF. We hypothesize that by alleviating oxidative stress in lung epithelial cells we can halt epithelial cell death and thus stop and reverse the progression of IPF. To test our hypothesis, we will treat lung epithelial cells with a pro-apoptotic signaling protein, Fas ligand (FasL), and measure levels of a key cellular oxidant, hydrogen peroxide (H2O2), in the ER. We will then assess the effects of modulating the activity of the most highly expressed ER H2O2 scavenger, peroxiredoxin 4 (Prdx4), on ER redox homeostasis and cell death. To further verify our findings, we will conduct studies using a mouse model of pulmonary fibrosis where we can induce the ablation of, Prdx4. Using this model, we will show the effects of decreasing cellular hydrogen peroxide levels on the development and progression of pulmonary fibrosis. Finally, we will verify that our findings are relevant to human IPF by conducting a similar set of experiments to access hydrogen peroxide levels and protein oxidation states in human IPF lung tissue. Upon completion of our research we will have a better grasp on the role of oxidative stress in the ER, which can be utilized to create more targeted antioxidant therapies for treatment of IPF.