MiR-23/27/24 Control of Adipose Tissue Macrophage Activation

总结 巨噬细胞是肥胖脂肪组织中最丰富的炎性细胞。它是建立在 动物模型表明，它们产生的促炎细胞因子驱动全身代谢功能障碍， 胰岛素抵抗是超重个体发病率和死亡率的主要原因。新兴 有证据表明，这种激活程序不同于经典的巨噬细胞激活， 细菌成分，因此提供了靶向治疗的潜力， 通过选择性抑制巨噬细胞的功能。发现调节这种变化的分子通路 独特激活程序是理解巨噬细胞生物学基本方面以及 将其转化为治疗优势在初步数据中，我们发现微RNA簇 miR-23、miR-24和miR-27的小分子RNA调控促炎细胞因子的产生， 模拟肥胖脂肪组织微环境的培养条件。该补助金提出的目标将 确定这组miRNAs在肥胖脂肪组织巨噬细胞中的功能， 巨噬细胞中由这些miRNA调控的基因网络。我们将使用完善的饮食诱导 肥胖小鼠模型与新产生的miRNA条件性敲除小鼠以及最新技术 RNA生物学的方法来研究调节这些的独特细胞和分子机制， 巨噬细胞肥胖影响了近40%的美国成年人口，并增加了患糖尿病的风险， 心血管疾病和癌症。最终，包括使用RNA疗法靶向 miRNAs及其基因网络可以提供一种新的方法来改变巨噬细胞的功能， 肥胖相关的炎症和减轻相关的慢性疾病的影响。

SUMMARY Macrophages are the most abundant inflammatory cell in obese adipose tissue. And it is well established in animal models that the pro-inflammatory cytokines they produce drive systemic metabolic dysfunction including insulin resistance, which is a major cause of morbidity and mortality in overweight individuals. Emerging evidence suggest that this activation program differs from classic macrophage activation in response to bacterial components, therefore offering the potential for targeted therapies to uncouple obesity from disease through the selective inhibition of macrophage function. Discovering the molecular pathways that regulate this unique program of activation are key to both understanding this basic facet of macrophage biology as well as leveraging it to therapeutic advantage. In preliminary data, we have found that the clusters of microRNAs (miRNAs) containing miR-23, miR-24 and miR-27 regulate the production of pro-inflammatory cytokines in culture conditions that model the obese adipose tissue microenvironment. The aims proposed in this grant will determine the function of this cluster of miRNAs in obese adipose tissue macrophages as well as define the network of genes regulated by these miRNAs in macrophages. We will use well-established diet induced obesity mouse models with newly generated miRNA conditional knock out mice as well as state-of-the-art approaches in RNA biology to investigate the unique cellular and molecular mechanisms that regulate these macrophages. Obesity affects nearly 40% of the adult population of the US and increases the risk of diabetes, cardiovascular disease and cancer. Ultimately, strategies including the use of RNA therapeutics to target miRNAs and their gene networks could offer a novel approach to modify macrophage function to control obesity-associated inflammation and mitigate the effects of associated chronic diseases.