Modulation of acute lung injury by tristetraprolin

三四脯氨酸对急性肺损伤的调节

• 批准号: 10078644
• 负责人: Sonika Patial
• 金额: $ 25.92万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-02 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078644
• 关键词: 3' Untranslated Regions; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar Macrophages; Binding; Binding Proteins; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Biology; Bone Marrow; Cell Lineage; Cells; Cessation of life; Chimera organism; Data; Development; Disease; Dose; Elements; Endotoxemia; Endotoxins; Exhibits; Functional disorder; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Hematopoietic; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Knock-in Mouse; Knowledge; Lung; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Neutrophil Infiltration; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Pneumonia; Post-Transcriptional Regulation; Process; Production; Pulmonary aspiration of gastric contents; Regulation; Research; Role; Secondary to; Sepsis; Serum; Stromal Cells; TIS11 protein; TNF gene; Testing; Therapeutic; Therapeutic Intervention; United States; Wild Type Mouse; adenylate; cecal ligation puncture; chemokine; cytokine; drug development; improved; lung injury; macrophage; mortality; novel; overexpression; polymicrobial sepsis; response; systemic inflammatory response; therapeutic development; transcriptome sequencing; transcriptomics; translational impact; uridylate

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.

项目摘要 败血症（间接ALI）的急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）为 毁灭性的条件，导致明显的发病率和死亡率。肺炎和胃抽吸 含量是直接急性肺损伤的两个主要原因（直接ALI），估计有55％的ARDS 是由直接肺损伤引起的。尽管阿里的病理生理学远未被理解，但 众所周知，促炎性细胞因子和趋化因子的产生起着核心作用。但是，它仍然是 尚不清楚如何调节这些促炎性介体。 Tristetraprolin（TTP）是mRNA结合蛋白 通过结合3'-非翻译 特定mRNA的区域（3'UTR）导致其快速营业额。小鼠中TTP的删除导致 TTP靶标mRNA（例如TNF）的稳定性介导的全身性炎症。沿着 相同的行，髓样特异性的TTP缺乏会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调节了调节的发病机理 阿里增强TTP水平可保护ALI；造血细胞TTP是必要的，足以 这个效果。我们将通过两个具体的目标检验我们的假设：在AIM 1中，我们将测试损失TTP的影响 （全身和髓样细胞单位）在直接和间接ALI的发病机理上。在AIM 2中，我们将测试 TTP的增强表达是否可以防止ALI的发展以及造血细胞是否 谱系特异性的TTP过表达是必要的，并且足以保护。总体目标 拟议的研究是通过提供药物理由来改善ALI（直接和间接）的治疗选择 针对细胞特异性稳定/增强TTP表达的开发。这些成功完成 研究将促进我们对TTP介导的基因转录后机制的作用的理解 调节ALI发病机理的表达。获得的知识将具有潜在的应用 鉴于TTP调节的mRNA为ALI的生物标志物和治疗性的发展 干预措施以提高TTP水平以治疗ALI。