Modulation of acute lung injury by tristetraprolin

项目摘要 继发于脓毒症的急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）（间接ALI） 一种导致严重发病率和死亡率的破坏性疾病。肺炎和胃误吸 内容物是直接急性肺损伤（direct acute lung injury，direct ALI）的两个主要原因，估计55%的ARDS 是由肺直接损伤引起的尽管ALI的病理生理学还远未被理解， 已知促炎性细胞因子和趋化因子的产生起中心作用。但委员会仍 目前尚不清楚这些促炎介质是如何调节的。Tristetraprolin（TTP）是一种mRNA结合蛋白， 通过结合3 '-非翻译区的腺苷酸-尿苷酸富集元件（战神）来调节mRNA水平。 区域（3 'UTR）的特定mRNA，导致其快速周转。小鼠中TTP的缺失导致 由TTP靶向mRNA如Tnf的稳定性增强介导的全身性炎症。沿着 相同的细胞系，骨髓特异性TTP缺乏导致对低剂量内毒素暴露的极端敏感性 导致内毒素血症和器官损伤的发展。因此，我们假设TTP 介导的促炎基因表达的转录后调节了 增加TTP水平可预防ALI;造血细胞TTP是治疗ALI的必要和充分条件。 这种效果。我们将通过两个具体目标来检验我们的假设：在目标1中，我们将检验TTP丧失的影响 （全身和骨髓细胞系）对直接和间接ALI发病机制的影响。在目标2中，我们将测试 TTP的表达增强是否能防止ALI的发展， 谱系特异性TTP过表达对于保护是必要且充分的。的总体目标 拟议的研究是通过提供药物治疗的基本原理来改善ALI（直接和间接）的治疗选择。 开发旨在细胞特异性稳定/增强TTP的表达。成功完成这些 这些研究将进一步加深我们对TTP介导的基因转录后机制的理解， 表达调控ALI的发病机制。获得的知识将有潜在的应用 为了鉴定TTP调节的mRNA作为ALI的生物标志物和开发治疗药物， 干预措施，以提高TTP水平治疗ALI。

Project Summary Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) secondary to sepsis (indirect ALI) is a devastating condition that results in a significant morbidity and mortality. Pneumonia and aspiration of gastric contents are the two major causes of direct acute lung injury (direct ALI) and it is estimated that 55% of ARDS is caused by direct lung injury. Although the pathophysiology of ALI is far from understood, exuberant production of pro-inflammatory cytokines and chemokines is known to play a central role. However, it remains unclear how these pro-inflammatory mediators are regulated. Tristetraprolin (TTP) is an mRNA binding protein that regulates mRNA levels by binding to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated regions (3'UTRs) of specific mRNAs resulting in their rapid turnover. Deletion of TTP in mice results in systemic inflammation that is mediated by enhanced stability of TTP target mRNAs, such as Tnf. Along the same lines, myeloid-specific TTP deficiency results in extreme sensitivity to low dose endotoxin exposure resulting in the development of endotoxemia and organ damage. Therefore, we hypothesize that TTP mediated post-transcriptional regulation of pro-inflammatory gene expression modulates the pathogenesis of ALI; enhancing TTP levels protects from ALI; and that hematopoietic-cell TTP is necessary and sufficient for this effect. We will test our hypothesis through two specific aims: In Aim 1, we will test the effect of loss of TTP (whole body and myeloid cell-lineage) on the pathogenesis of direct and indirect ALI. In Aim 2, we will test whether enhanced expression of TTP protects against the development of ALI and whether hematopoietic cell lineage-specific TTP overexpression is necessary and sufficient for protection. The overall goal of the proposed research is to improve therapeutic options in ALI (direct and indirect) by providing rationale for drug development aimed at cell-specific stabilization/enhanced expression of TTP. Successful completion of these studies will advance our understanding of the role of TTP mediated post-transcriptional mechanisms of gene expression in regulating the pathogenesis of ALI. The knowledge gained will have potential applications towards the identification of TTP-regulated mRNAs as biomarkers of ALI and the development of therapeutic interventions to enhance TTP levels for the treatment of ALI.