Regulation of SYSTEMIC INSULIN SENSITIVITY by miRNA-30a

miRNA-30a 对全身胰岛素敏感性的调节

基本信息

批准号：
9111200
负责人：
Sean Hartig
金额：
$ 7.93万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111200
关键词：
Address Adipocytes Adipose tissue Adult Affect Antibodies Biology Calories Child Complement Complex Data Defect Diabetic mouse Energy Metabolism Etiology Fatty acid glycerol esters Flow Cytometry Foundations Functional disorder Funding Gene Expression Regulation Gene Targeting Goals Human Immune Immune response Inflammation Inflammatory Insulin Insulin Resistance Laboratories Lead Link Mediating Mentors Metabolic Metabolic Control Metabolism MicroRNAs Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Phenotype Physiology Population Regulation Regulatory T-Lymphocyte Reporting Research Role Solid T-Lymphocyte Testing Therapeutic Training Transcript Work base cell type diabetic energy balance flexibility human subject improved in vivo Model insulin sensitivity knock-down macrophage novel novel strategies novel therapeutics overexpression prevent programs public health relevance response subcutaneous transcriptome sequencing

Address Adipocytes Adipose tissue Adult Affect Antibodies Biology Calories Child Complement Complex Data Defect Diabetic mouse Energy Metabolism Etiology Fatty acid glycerol esters Flow Cytometry Foundations Functional disorder Funding Gene Expression Regulation Gene Targeting Goals Human Immune Immune response Inflammation Inflammatory Insulin Insulin Resistance Laboratories Lead Link Mediating Mentors Metabolic Metabolic Control Metabolism MicroRNAs Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Phenotype Physiology Population Regulation Regulatory T-Lymphocyte Reporting Research Role Solid T-Lymphocyte Testing Therapeutic Training Transcript Work base cell type diabetic energy balance flexibility human subject improved in vivo Model insulin sensitivity knock-down macrophage novel novel strategies novel therapeutics overexpression prevent programs public health relevance response subcutaneous transcriptome sequencing

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项目摘要

DESCRIPTION (provided by applicant): Insulin resistance and type 2 diabetes are predicted to affect 33% of the US population by 2050. Type 2 diabetes reflects the inability to store surplus energy derived from calories in fat cells. Obese fat displays a pro-inflammatory phenotype, which is partly responsible for the metabolic dysfunction and insulin resistance that precedes type 2 diabetes. Recent work challenges the idea that the all immune response is deleterious to adipose tissue. In particular, regulatory T cells (Tregs) counteract the proinflammatory response in adipose tissue to potentiate insulin sensitivity. We have discovered that overexpression of the microRNA miR-30a in subcutaneous adipose tissue of diabetic mice promotes insulin sensitivity. Through the use of RNA-seq and flow cytometry, we observed that the metabolic effects of miR-30a overexpression in subcutaneous adipose tissue are associated with increased recruitment of Tregs, which suppress local inflammation. In addition, we found that expression of miR-30a and the master controller of Treg function, Foxp3, are reduced in subcutaneous adipose tissue from insulin resistant compared to insulin sensitive human subjects. We hypothesize miR-30a promotes insulin sensitivity by stimulating the function of Tregs in subcutaneous adipose tissue. Two specific aims are proposed to critically test our hypothesis: (1) determine the role of Tregs in mediating anti-diabetic effects of miR-30a; (2) determine how miR-30a affects Treg polarization. The rationale for the proposed research plan is that identifying the mechanism underlying the beneficial effects of miR-30a expression in subcutaneous adipose tissue will lead to therapeutic strategies to enhance metabolic flexibility in subcutaneous adipocytes and thereby prevent type 2 diabetes. If our hypothesis is true, miR-30a might be exploited in novel therapies to manage insulin resistance and type 2 diabetes. We anticipate that our studies will provide new clues into the complex regulatory networks controlling energy balance in subcutaneous adipose tissue.

描述（由应用提供）：预计到2050年，预计胰岛素抵抗和2型糖尿病会影响美国人群的33％。2型糖尿病反映出无法储存脂肪细胞中卡路里的多余能量。肥胖脂肪显示出促炎的表型，该表型部分负责2型糖尿病之前的代谢功能障碍和胰岛素抵抗。最近的工作挑战了所有免疫反应对脂肪组织有害的想法。特别是，调节性T细胞（Tregs）抵消了脂肪组织中对潜在胰岛素敏感性的促炎反应。我们发现，糖尿病小鼠皮下脂肪组织中microRNA miR-30a的过表达促进了胰岛素敏感性。通过使用RNA-seq和流式细胞仪，我们观察到MiR-30a在皮下脂肪组织中过表达的代谢作用与抑制局部炎症的Treg募集的增加有关。此外，我们发现与胰岛素敏感的人类受试者相比，在皮下脂肪组织中，miR-30a和Treg功能的主控制器FOXP3的表达降低了。我们假设miR-30a通过刺激Treg在皮下脂肪组织中的功能来促进胰岛素敏感性。提出了两个具体的目的来批判性地检验我们的假设：（1）确定Treg在介导miR-30a的抗糖尿病作用中的作用；（2）确定miR-30a如何影响Treg极化。拟议的研究计划的理由是，确定miR-30a表达在皮下脂肪组织中的有益作用的机制将导致治疗策略，以增强皮下脂肪细胞中代谢灵活性，从而预防2型糖尿病。是的，可以在治疗胰岛素抵抗和2型糖尿病的新型疗法中探索miR-30a。我们预计我们的研究将为控制皮下脂肪组织中能量平衡的复杂调节网络提供新的线索。