Targeting Myeloid Dependent MicroRNAs in Acute Respiratory Distress Syndrome

靶向骨髓依赖性 MicroRNA 治疗急性呼吸窘迫综合征

• 批准号: 10367161
• 负责人: Xiaoyi Yuan
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367161
• 关键词: 3' Untranslated Regions; Acute; Acute Respiratory Distress Syndrome; Address; Anti-Inflammatory Agents; Attenuated; Binding; Biological Assay; Biological Process; Clinical Trials; Complex; Cytokine Gene; Data; Development; Disease; Genes; Genetic; Genetic Transcription; Goals; Histones; Human; Human Genome; Hypermethylation; Hypoxia Inducible Factor; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Interleukin-6; Kinetics; Leukocytes; LoxP-flanked allele; Luciferases; Lung; Lung infections; Mediating; Metabolism; Methylation; MicroRNAs; Mitochondria; Mus; Myelogenous; Myeloid Cells; Pathogenesis; Pathway interactions; Phase I Clinical Trials; Phenotype; Post-Transcriptional Regulation; Process; Production; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Inflammation; Recovery; Regulation; Reporter; Repression; Research; Resolution; Role; Small Interfering RNA; Structure of parenchyma of lung; Succinates; TNF gene; Testing; Therapeutic; Transcriptional Regulation; Transgenic Mice; Translating; Work; base; cytochrome c oxidase; cytokine; design; experimental study; hypoxia inducible factor 1; improved; in silico; in vivo; innovation; intravenous injection; loss of function; lung injury; macrophage; mouse model; nanoparticle; new therapeutic target; novel; overexpression; oxidation; promoter; recruit; response; screening; therapeutic target; tissue injury; transcription factor; transcriptome sequencing

Abstract Lung inflammation is one of the profound contributors to acute respiratory distress syndrome (ARDS). The initial acute lung inflammation in response to infection or tissue injury leads to profound infiltration of leukocytes and the release of inflammatory cytokines. Myeloid cells, including macrophages, are key players mediating the onset and resolution of acute lung inflammation. However, the triggers that reprogram macrophages to control excessive inflammation remain incompletely understood. Recent work has demonstrated a key role for microRNAs (miRNAs) in inflammatory diseases. However, little research has been done to assess the functional role of miRNAs in macrophages in the context of controlling lung inflammation. We hypothesize that control of lung inflammation involves the transcriptional induction of specific miRNAs in macrophages. Our study has identified microRNA-147 (miR-147) to be dramatically increased in recruited macrophages during lung inflammation. The induction of miR-147 is dependent on hypoxia-inducible factor 1A. Functionally, miR- 147 controls macrophage inflammation in vitro, and myeloid-derived miR-147 dampens lung inflammation in vivo. We identified and confirmed the mitochondria complex associated protein NDUFA4 as a leading miR-147 target. New and exciting preliminary data indicated that by targeting NDUFA4, miR-147 dampens the production of inflammatory cytokines such as IL-6, IL-1β, and TNFα in macrophages. Additional evidence supports that inhibition of succinate oxidation and concomitant histone hypermethylation contributes to the miR-147/NDUFA4 mediated effect. Finally, overexpression of miR-147 improves the recovery from lung inflammation in vivo. Here, we test the hypothesis that the miR- 147/NDUFA4 axis represents an endogenous protective pathway in macrophages to control lung inflammation. The following three aims have been proposed to test this hypothesis. In Aim 1, we will use state-of-art miR- 147 reporter mice to study the transcriptional regulation of miR-147 and investigate how miR- 147/NDUFA4 axis controls macrophage inflammation in vitro. In Aim 2, we will perform proof-of-principle studies in human ARDS and employ cutting-edge transgenic mice to investigate the functional role of miR-147/NDUFA4 axis in macrophages during lung inflammation in vivo. In Aim 3, we will further explore the therapeutic targeting of miR-147/NDUFA4 axis in modulating lung inflammation. The completion of the proposed study will identify miRNA targets as an innovative therapeutic approach for ARDS.

抽象的 肺部炎症是导致急性呼吸窘迫综合征（ARDS）的深刻贡献者之一。这 响应感染或组织损伤的初始急性肺部感染导致白细胞浸润 以及炎症细胞因子的释放。包括巨噬细胞在内的髓样细胞是介导的关键参与者 急性肺部感染的发作和分辨率。但是，将巨噬细胞重新编程为 控制过多的炎症仍然不完全理解。最近的工作表明了 炎症性疾病中的microRNA（miRNA）。但是，很少进行研究来评估 在控制肺注射的背景下，miRNA在巨噬细胞中的功能作用。我们假设这一点 对肺注射的控制涉及巨噬细胞中特定miRNA的转录诱导。我们的 研究已经确定MicroRNA-147（miR-147）在招募的巨噬细胞中会显着增加 肺部炎症。 miR-147的诱导取决于缺氧诱导因子1a。在功能上，mir- 147控制体外巨噬细胞炎症，髓样衍生的miR-147抑制肺 体内炎症。我们确定并确认了线粒体复合物相关蛋白 NDUFA4作为主要的miR-147目标。新的令人兴奋的初步数据表明，通过定位 NDUFA4，miR-147抑制了炎性细胞因子（例如IL-6，IL-1β和TNFα）的产生 巨噬细胞。其他证据支持抑制琥珀酸酯氧化和伴随的证据 Hisstone高甲基化有助于miR-147/NDUFA4介导的效应。最后，过表达 miR-147改善了体内肺注射的回收率。在这里，我们检验了mir-的假设 147/NDUFA4轴代表巨噬细胞中的内源性保护途径，以控制肺部注射。 已经提出了以下三个目标来检验这一假设。在AIM 1中，我们将使用最先进的mir- 147个记者小鼠研究miR-147的转录调节，并研究miR-如何 147/NDUFA4轴在体外控制巨噬细胞注射。在AIM 2中，我们将执行原理证明 人类ARDS和员工前沿转基因小鼠研究的研究 在体内肺注射过程中巨噬细胞中的miR-147/ndufa4轴。在AIM 3中，我们将进一步探索 MiR-147/NDUFA4轴的治疗靶向调节肺注射。完成 拟议的研究将确定miRNA靶标是ARDS的创新治疗方法。