Metabolic regulation of macrophage microRNAs during colitis

项目摘要 巨噬细胞在炎症性疾病如结肠炎中发挥重要作用，能够促进 并根据情况抑制炎症。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是重要的。两种生物调节剂， 在巨噬细胞身份和功能能力中起关键作用的是microRNAs（miRNAs）和代谢。 这两种主要的细胞功能调节剂如何相互作用一直是最近感兴趣的话题。 虽然有几项研究探讨了miRNAs如何调节代谢途径，但很少有人探讨miRNAs如何调节代谢途径。 代谢调节miRNA的表达和功能。我们的初步数据表明，去甲氨醇解是一种 巨噬细胞中miRNA表达的主要调节因子。一组miRNAs似乎与 受多巴胺分解影响的是miR 125 a/miR 99 b/Let 7 e簇，其在阻断后显著减少 去乙酰氨基酶根据我们的初步结果，转录因子Hif 1a似乎是一个关键的联系， miR 125 a/miR 99 b/Let 7 e簇转录。在这些有希望的初步重建的基础上， 结果，我们将使用生化方法和新开发的转基因小鼠模型开始检查 谷氨酰胺分解如何以及为什么调节这个突出的miRNA簇的表达。此外，我们将利用 小鼠结肠炎模型来研究这种新的调节机制在炎症性疾病的背景下。结果 这项工作将为miRNAs在先天免疫中如何受细胞代谢调节提供新的线索。 系统这些结果将填补我们对免疫调节知识的重大空白，并为开发人员提供信息。 新的治疗方法旨在调节miRNAs以对抗人类疾病。

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.