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.

项目摘要/摘要代谢综合征（MetS），疾病和疾病的星座，包括肥胖，胰岛素抗性/异常葡萄糖调节，非酒精性脂肪肝病（NAFLD），循环LDL- C/HDL-C比和甘油三酸酯以及高血压正在迅速增加，并且与更严重的疾病，例如2型糖尿病和心血管疾病。但是，遗传和分子对MetS病因的贡献尚不清楚。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协会研究（GWAS）揭示了与胆固醇/脂质异常，肥胖，类型有关的miR-128-1 microRNA 2种糖尿病和最近的人类积极选择。我们在小鼠的体外和体内研究的初步研究确认miR-128-1对代谢稳态产生了深远的影响。我们在这里建议测试 mir-128-1代表哺乳动物能量代谢的中心调节剂，并且人类的假设远古时代对盛宴/饥荒周期的进化适应导致miR-128-1活性促进在某些人类人群中存储能源。虽然在饥荒时期有益，但mir-128-1升高当前的活动/水平在发达国家中充满了粮食丰富的活动可能有助于肥胖和2型糖尿病等代谢疾病。小鼠体外细胞培养和体内研究具有miR-128-1的反义靶向的代谢疾病模型（例如DIO，OB/OB小鼠）以及miR-128-1 KO小鼠将提供有关miR-128-1在靶向指导途径中的作用的关键机理见解代谢稳态，以及该microRNA是否适合治疗靶向改进普遍的代谢性疾病，例如肥胖和2型糖尿病。