Metabolic regulation of macrophage microRNAs during colitis

结肠炎期间巨噬细胞 microRNA 的代谢调节

• 批准号: 10285819
• 负责人: Ryan M O'Connell
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-26 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285819
• 关键词: Activities of Daily Living; Anti-Inflammatory Agents; Behavior; Binding Sites; Biochemical; Biological; Biological Process; Biology; Cell physiology; Cells; Colitis; Data; Development; Disease; Gastrointestinal tract structure; Genes; Genetic Models; Genetic Transcription; Glutamine; Heart Diseases; Host Defense; Immune; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Knowledge; Light; Link; Literature; Mediating; Metabolic; Metabolic Pathway; Metabolism; MicroRNAs; Nucleic Acid Regulatory Sequences; Obesity; Pathway interactions; Play; Predisposition; Production; Reagent; Regulation; Role; Signal Pathway; Succinates; Testing; Transgenic Mice; Work; base; combat; conditional knockout; human disease; immunoregulation; in vivo; interest; macrophage; mouse model; novel; novel therapeutic intervention; response; small molecule; therapeutic RNA; therapeutic target; transcription factor

Project Summary Macrophages play an important role during inflammatory diseases such as colitis, being able to both promote and suppress inflammation depending on the context. Therefore, understanding ways to control macrophage behavior is important for understanding how to modulate inflammatory responses. Two biological regulators that play a critical role in macrophage identity and functional capacity are microRNAs (miRNAs) and metabolism. How these two major regulators of cellular function interact with each other has been a topic of recent interest. While several studies have explored how miRNAs regulate metabolic pathways, far fewer have explored how metabolism regulates miRNA expression and function. Our preliminary data indicate that glutaminolysis is a major regulator of miRNA expression in macrophages. One cluster of miRNAs that appears to be significantly impacted by glutaminolysis is the miR125a/miR99b/Let7e cluster, which is significantly reduced upon blockade of glutaminolysis. Based on our preliminary results, the transcription factor Hif1a appears to be a key link between glutaminolysis and miR125a/miR99b/Let7e cluster transcription. To build upon these promising preliminary re- sults, we will use biochemical approaches and newly developed transgenic mouse models to begin to examine how and why glutaminolysis regulates the expression of this prominent miRNA cluster. Further, we will utilize a mouse model of colitis to study this novel regulatory mechanism in the context of inflammatory disease. Results from this work will shed new light on how miRNAs are regulated by cellular metabolism in the innate immune system. These results will both fill a major gap in our knowledge of immune regulation, and inform the develop- ment of new therapeutic approaches aimed at modulating miRNAs to combat human disease.

项目摘要 巨噬细胞在结肠炎等炎症性疾病中起着重要作用，它既能促进 并根据具体情况抑制炎症。因此，了解控制巨噬细胞的方法 行为对于理解如何调节炎症反应很重要。两种生物调节剂 在巨噬细胞识别和功能能力中起关键作用的是microRNAs(MiRNAs)和代谢。 这两个细胞功能的主要调节因子如何相互作用一直是最近感兴趣的话题。 虽然有几项研究探索了miRNAs是如何调节代谢途径的，但很少有人研究miRNAs如何调控代谢途径 代谢调节miRNA的表达和功能。我们的初步数据表明，谷氨酰胺分解是一种 巨噬细胞miRNA表达的主要调节因子。一簇miRNAs似乎显著 受谷氨酰胺分解影响的是miR125a/miR99b/Let7e簇，阻断后该簇显著减少 谷氨酰胺分解。根据我们的初步结果，转录因子HIF1a似乎是 谷氨酰胺分解和miR125a/miR99b/Let7e簇转录。在这些有希望的初步研究的基础上- 结果，我们将使用生化方法和新开发的转基因小鼠模型来开始检测 谷氨酰胺分解如何以及为什么调节这个重要的miRNA簇的表达。此外，我们还将利用 建立小鼠结肠炎模型，研究炎症性疾病背景下这一新的调控机制。结果 这项工作将对miRNAs如何在先天性免疫中由细胞新陈代谢进行调节提供新的线索。 系统。这些结果都将填补我们在免疫调节知识方面的一个重大空白，并为以下研究提供信息： 开发新的治疗方法，旨在调节miRNAs以抗击人类疾病。