A thrifty microRNA in insulin resistance and Type 2 diabetes

胰岛素抵抗和 2 型糖尿病中节俭的 microRNA

基本信息

批准号：
9364401
负责人：
ANDERS M NAAR
金额：
$ 36万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9364401
关键词：
Address Adult Agriculture Albumins Animals Antisense Oligonucleotides Blood Chemical Analysis Cardiovascular Diseases Cell Culture Techniques Cholesterol Consumption Creatinine Cytomegalovirus Data Development Diabetes Mellitus Diet Disease Disease model Dose Energy Intake Energy Metabolism Enzymes Etiology Euglycemic Clamping Famines Fatty acid glycerol esters Food Functional disorder Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Translation Genetic study Genomics Glucose Hepatic High Density Lipoproteins Histologic Homeostasis Human Human Genetics Human Genome Hypertension Hypertriglyceridemia Impairment In Vitro Individual Insulin Insulin Resistance Integration Host Factors Investigation Kidney Knockout Mice Lactase Link Lipids Liver Low-Density Lipoproteins Medicine Metabolic Metabolic Control Metabolic Diseases Metabolic syndrome Metabolism MicroRNAs Milk Modality Molecular Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nucleotides Obese Mice Obesity Pathway interactions Population Prevention Protein Inhibition Recovery Regimen Regulation Rodent Model Role Science Skeletal Muscle Staining method Stains Testing Therapeutic Time Tissues Toxic effect Translational Research Translations Triglycerides Visceral base blood glucose regulation blood lipid cholesterol control genetic association genome wide association study glucose production glucose tolerance glucose uptake improved in vivo insight insulin sensitivity insulin tolerance lipid metabolism mRNA Transcript Degradation metabolomics mouse model non-alcoholic fatty liver novel novel therapeutics precision medicine programs sedentary lifestyle subcutaneous therapeutic target transcription factor transcriptome sequencing translational medicine validation studies

项目摘要

Project Summary/Abstract The metabolic syndrome (MetS), a constellation of conditions and disorders including obesity, insulin resistance/abnormal glucose regulation, nonalcoholic fatty liver disease (NAFLD), elevated circulating LDL- C/HDL-C ratios and triglycerides, and hypertension, is rapidly increasing world-wide and is associated with more severe diseases such as type 2 diabetes and cardiovascular disease. However, the genetic and molecular contributions to the etiology of MetS remain unclear. We recently discovered microRNAs (miR- 33b/a) as key regulators of cholesterol/lipid homeostasis. We have now employed genome-wide association studies (GWAS) to uncover the miR-128-1 microRNA as linked to cholesterol/lipid abnormalities, obesity, type 2 diabetes and recent human positive selection. Our preliminary in vitro and in vivo studies in mice have confirmed that miR-128-1 exerts profound effects on metabolic homeostasis. We propose here to test the hypothesis that miR-128-1 represents a central regulator of mammalian energy metabolism, and that human evolutionary adaptation to feast/famine cycles in ancient times led to increased miR-128-1 activity promoting energy storage in certain human populations. While beneficial in times of famine, elevated miR-128-1 activity/levels in present times with profound food abundance in the developed world could contribute to metabolic diseases such as obesity and type 2 diabetes. Both in vitro cell culture and in vivo studies in mouse metabolic disease models (e.g., DIO, ob/ob mice) with antisense targeting of miR-128-1, as well as miR-128-1 KO mice will provide critical mechanistic insights into the role of miR-128-1 in targeting pathways guiding metabolic homeostasis, and whether this microRNA may be suitable for therapeutic targeting to improve prevalent metabolic disorders such as obesity and type 2 diabetes.

项目概要/摘要代谢综合征 (MetS)，是一系列病症和疾病，包括肥胖、胰岛素抵抗力/血糖调节异常、非酒精性脂肪肝 (NAFLD)、循环 LDL- 升高 C/HDL-C 比率和甘油三酯以及高血压在世界范围内迅速增加，并且与更严重的疾病，如2型糖尿病和心血管疾病。然而，遗传和 MetS 病因学的分子贡献仍不清楚。我们最近发现了 microRNA（miR- 33b/a) 作为胆固醇/脂质稳态的关键调节剂。我们现在采用了全基因组关联研究 (GWAS) 发现 miR-128-1 microRNA 与胆固醇/脂质异常、肥胖、类型有关 2 糖尿病和近期人类积极选择。我们对小鼠进行的初步体外和体内研究证实 miR-128-1 对代谢稳态具有深远影响。我们建议在这里测试假设 miR-128-1 代表哺乳动物能量代谢的中心调节因子，而人类古代对盛宴/饥荒周期的进化适应导致 miR-128-1 活性增加，促进某些人群的能量储存。虽然 miR-128-1 升高对饥荒时期有益，但当前发达国家食物丰富的活动/水平可能有助于代谢性疾病，例如肥胖和2型糖尿病。体外细胞培养和小鼠体内研究具有 miR-128-1 反义靶向的代谢疾病模型（例如 DIO、ob/ob 小鼠）以及 miR-128-1 KO 小鼠将为 miR-128-1 在靶向途径指导中的作用提供重要的机制见解代谢稳态，以及这种 microRNA 是否适合用于治疗靶向以改善常见的代谢性疾病，如肥胖和 2 型糖尿病。