Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury

靶向 MicroRNA miR-122 治疗围手术期肝损伤

• 批准号: 10598586
• 负责人: Holger K. Eltzschig
• 金额: $ 44.51万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598586
• 关键词: Acute; Address; Attenuated; Binding; Biological Assay; Cadaver; Cell Line; Clinical Research; Excision; Exposure to; Family; Gene Expression; Genes; Genetic Transcription; Goals; HIF1A gene; Hepatic; Hepatic Tissue; Hepatitis C virus; Hepatocyte; Human; Hypoxia; Injury; Length; Liver; Living Donor Liver Transplantation; Mediating; MicroRNAs; Modality; Morbidity - disease rate; Mus; Nucleotides; Operative Surgical Procedures; Oxygen; Pathway interactions; Patients; Perioperative; Procollagen-Proline Dioxygenase; Reperfusion Injury; Reperfusion Therapy; Repression; Resistance; Role; Signal Transduction; Small Interfering RNA; Source; Therapeutic; Transcriptional Regulation; Translating; Untranslated RNA; Up-Regulation; attenuation; design; graft failure; inhibitor; innovation; ischemic injury; lentiviral-mediated; liver biopsy; liver injury; liver ischemia; liver transplantation; mortality; mouse model; nanoparticle; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; posttranscriptional; prevent; promoter; protein expression; reconstitution; safety and feasibility; tissue injury; transcription factor

PROJECT SUMMARY The goal of this proposal is to identify microRNA (miRNA) targets as innovative therapeutic approach for the treatment of hepatic ischemia and reperfusion injury. Hepatic ischemia and reperfusion injury is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. MiRNAs constitute a family of noncoding RNA molecules of 20 to 25 nucleotides in length that regulate gene expression at the posttranscriptional level. In order to identify functionally important miRNAs during hepatic ischemia and reperfusion, we performed a targeted miRNA screen in a murine model of liver ischemia. We observed the most dramatic increase in miRNA expression for miR-122 – a liver-specific miRNA that is functionally implicated in the propagation of the hepatitis C virus. Subsequent studies of hepatic ischemia and reperfusion injury in mice with hepatocyte-specific deletion of miR-122 revealed dramatic increases in hepatic tissue injury. Utilization of a hepatocyte cell line with lentiviral-mediated overexpression of miR-122 allowed us to identify the oxygen-sensing prolyl-hydroxylase PHD1 as a novel target gene for miR-122. Thus, we hypothesize that HIF1A-dependent induction of miR-122 represents a feed-forward pathway for liver protection that enhances hypoxia-elicited liver protection via repression of its target gene PHD1.

项目概要 该提案的目标是确定 microRNA (miRNA) 靶标作为创新治疗方法 治疗肝缺血再灌注损伤具有重要意义。 主要肝切除术和肝移植期间发病率和死亡率的来源。 构成调节基因表达的长度为 20 至 25 个核苷酸的非编码 RNA 分子家族 在转录后水平上鉴定肝缺血和肝损伤期间功能重要的 miRNA。 再灌注后，我们在小鼠肝缺血模型中进行了靶向 miRNA 筛选。 miR-122 的 miRNA 表达显着增加，miR-122 是一种肝脏特异性 miRNA，具有功能性 与丙型肝炎病毒的传播有关。随后的肝缺血和再灌注研究。 肝细胞特异性删除 miR-122 的小鼠的损伤表明，肝组织损伤显着增加。 利用慢病毒介导的 miR-122 过表达肝细胞系使我们能够鉴定 氧敏感脯氨酰羟化酶 PHD1 作为 miR-122 的新靶基因因此，我们努力做到这一点。 miR-122 的 HIF1A 依赖性诱导代表了一种增强肝脏保护的前馈途径 缺氧通过抑制其靶基因 PHD1 引起肝脏保护。