Modulation of acute lung injury by tristetraprolin

项目摘要 继发于脓毒症(间接ALI)的急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS) 一种毁灭性的状况，导致严重的发病率和死亡率。肺炎与胃误吸 内容物是直接急性肺损伤(DIRECT ALI)的两个主要原因，据估计，55%的ARDS 是由直接肺损伤引起的。虽然ALI的病理生理机制还远未被了解，但仍很活跃 已知促炎细胞因子和趋化因子的产生起着核心作用。然而，它仍然 目前尚不清楚这些促炎介质是如何受到监管的。雷公藤红素(Tristetraprolin，TTP)是一种mRNA结合蛋白 它通过与3‘-未翻译的腺苷酸尿酸富含元件(ARE)结合来调节mRNA水平 特定mRNAs的3个区域(3‘UTRs)导致其快速周转。TTP在小鼠中的缺失导致 全身性炎症，由TTP靶向mRNAs的稳定性增强所介导，如肿瘤坏死因子。沿着这条路 同样，髓系特异性TTP缺乏会导致对低剂量内毒素暴露的极度敏感 导致内毒素血症的发展和器官损伤。因此，我们假设TTP 促炎症基因表达的转录后调控调控血管内皮细胞瘤的发病机制 提高TTP水平可预防ALI；而造血细胞TTP是治疗ALI的必要条件和充分条件 这种效果。我们将通过两个具体目标来验证我们的假设：在目标1中，我们将测试TTP丢失的效果 (全身和髓系)对直接和间接ALI发病机制的探讨。在目标2中，我们将测试 TTP表达增强对ALI及造血细胞是否有保护作用 谱系特异性TTP的过度表达对于保护是必要的，也是足够的。该计划的总体目标 建议的研究是通过提供药物的理论基础来改善ALI的治疗选择(直接和间接) 针对细胞特异性稳定/增强TTP表达的研究进展。成功完成这些任务 研究将促进我们对TTP介导的基因转录后机制的理解 在调节ALI发病机制中的表达。所获得的知识将具有潜在的应用价值。 TTP调控的mRNAs作为ALI生物标志物的鉴定及治疗进展 提高ALI治疗中TTP水平的干预措施。

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.