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

MiR-23/27/24 控制脂肪组织巨噬细胞激活

基本信息

批准号：
10392850
负责人：
Heather H Pua
金额：
$ 22.2万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392850
关键词：
Adipose tissue Adopted Adult Affect Animal Model Binding Sites Biology Cardiovascular Diseases Cell physiology Cells Chronic Chronic Disease Data Disease Environment Exposure to Fatty Acids Fatty acid glycerol esters Gene Expression Gene Expression Profile Genes Genetic Transcription Glucose Goals Grant Immune Immunology In Vitro Individual Infection Inflammation Inflammatory Insulin Insulin Resistance Interleukin-1 Interleukin-12 Interleukin-6 Knockout Mice Link Macrophage Activation Malignant Neoplasms Mediating Messenger RNA Metabolic Metabolic Activation Metabolic dysfunction MicroRNAs Modeling Molecular Molecular Target Morbidity - disease rate Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Obesity Overnutrition Overweight PPAR gamma Palmitates Pathogenesis Pathway interactions Phenotype Population Production RNA Role T cell differentiation TNF gene Testing Therapeutic Tissues Up-Regulation Work allergic airway inflammation conditional knockout cytokine diabetes risk diet-induced obesity effector T cell endoplasmic reticulum stress gene network inhibitor macrophage mortality mouse model novel novel strategies programs response targeted treatment transcription factor

项目摘要

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.

概括巨噬细胞是肥胖脂肪组织中最丰富的炎症细胞。它已经建立了促炎性细胞因子产生的动物模型，它们驱动全身代谢功能障碍包括胰岛素抵抗，这是超重个体发病率和死亡率的主要原因。新兴有证据表明，该激活程序与经典的巨噬细胞激活有所不同。细菌成分，因此提供了靶向疗法使肥胖与疾病脱离的潜力通过选择性抑制巨噬细胞功能。发现调节这一点的分子途径独特的激活程序既是理解巨噬细胞生物学的基本方面的关键利用它具有治疗优势。在初步数据中，我们发现microRNA的簇（miRNA）含有miR-23，miR-24和miR-27调节促炎细胞因子在中的产生对肥胖脂肪组织微环境进行建模的培养条件。这笔赠款中提出的目标将确定该miRNA簇在肥胖脂肪组织巨噬细胞中的功能，并定义这些miRNA在巨噬细胞中调节的基因网络。我们将使用公认的饮食肥胖小鼠模型具有新生成的miRNA条件敲除小鼠以及最先进的 RNA生物学的方法研究了调节这些调节的独特细胞和分子机制巨噬细胞。肥胖症影响了近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疗法来针对的策略 miRNA及其基因网络可以提供一种新的方法来修改巨噬细胞功能以控制肥胖相关的炎症并减轻相关慢性疾病的影响。