Regulation of cholesterol/lipid homeostasis by microRNA-33a/b

microRNA-33a/b 调节胆固醇/脂质稳态

基本信息

批准号：
8856224
负责人：
ANDERS M NAAR
金额：
$ 37.53万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-24 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856224
关键词：
3&apos Untranslated Regions ADD-1 protein ATP binding cassette transporter 1 Address Affect Antisense Oligonucleotides Binding Proteins Biological Assay Cardiovascular Diseases Cell Culture Techniques Cells Cercopithecus pygerythrus Cholesterol Cholesterol Homeostasis Code Cues DNA Microarray Chip Data Diet Disease Enzymes Fatty Acids Feedback Gene Expression Gene Proteins Genes Genome Glucose HDL-triglyceride Health HepG2 High Density Lipoproteins Homeostasis Human Hypertriglyceridemia In Vitro Individual Injection of therapeutic agent Insulin Insulin Resistance Light Lipids Liver Low-Density Lipoproteins Mediating Metabolic Metabolic Control Metabolic syndrome MicroRNAs Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oligonucleotides Pathway interactions Patients Plasma Production Protein Family Regulation Regulatory Element Role SRE-1 binding protein Signal Transduction Sterols Stress Testing Therapeutic Translations Triglycerides adenylate kinase base cholesterol control cholesterol transporters combat design feeding improved in vivo inhibitor/antagonist insight lipid biosynthesis lipid metabolism lipoprotein triglyceride member nonhuman primate novel strategies novel therapeutics oxidation protein function response sensor therapeutic target trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Accurate regulation of cholesterol/lipid homeostasis is essential to human health. Indeed, high circulating LDL- to-HDL ratios and elevated triglycerides are associated with metabolic syndrome, type II diabetes, and cardiovascular disease (CVD). An improved understanding of the regulatory mechanisms governing circulating levels of HDL and triglycerides could yield novel therapeutic avenues to combat cardiometabolic disorders. We recently made the surprising discovery that the human SREBP-1 and -2 genes encoding key transcriptional regulators of cholesterol/lipid biosynthesis harbor intronic microRNAs (miR-33b and miR-33a, respectively). Intriguingly, miR-33a/b represent key inhibitors of the ABCA1 cholesterol transporter and HDL synthesis to boost intracellular cholesterol levels, and injection of antisense oligonucleotides directed against miR-33a significantly increases HDL levels in mice on a western-type diet. We propose here to test the hypothesis that miR-33a/b represent central regulators of multiple aspects of mammalian cholesterol/lipid metabolism, in close cooperation with the SREBP host genes. Both in vitro cell culture and in vivo studies in mice and non-human primates will provide key mechanistic insights into the role of miR-33a/b in targeting entire pathways guiding lipid and energy homeostasis, and whether miR-33a/b may be suitable for therapeutic targeting to raise circulating HDL and lower plasma triglycerides in metabolic syndrome patients.

描述（由申请人提供）：准确调节胆固醇/脂质稳态对人类健康至关重要。实际上，高循环的LDL-HDL比和甘油三酸酯升高与代谢综合征，II型糖尿病和心血管疾病（CVD）有关。对管理HDL和甘油三酸酯循环水平的调节机制有了改进的理解，可以产生新型的治疗途径，以打击心脏代谢性疾病。我们最近提出了一个令人惊讶的发现，即编码胆固醇/脂质生物合成的关键转录调节剂的人类SREBP-1和-2基因内含子MicroRNA（MIR-33B和MIR-33A）。有趣的是，miR-33a/b代表了对ABCA1胆固醇转运蛋白和HDL合成的关键抑制剂，以提高细胞内胆固醇水平，并注入针对miR-33a的反义寡核苷酸的注射，可显着提高西方饮食中小鼠HDL水平的抗义寡核苷酸。我们在这里提议检验以下假设：miR-33a/b代表与SREBP宿主基因密切合作的哺乳动物胆固醇/脂质代谢多个方面的中心调节剂。 Both in vitro cell culture and in vivo studies in mice and non-human primates will provide key mechanistic insights into the role of miR-33a/b in targeting entire pathways guiding lipid and energy homeostasis, and whether miR-33a/b may be suitable for therapeutic targeting to raise circulating HDL and lower plasma triglycerides in metabolic syndrome patients.

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-atherosclerosis or No Anti-atherosclerosis: That is the miR-33 question.

DOI：
10.1161/atvbaha.112.301021
发表时间：
2013-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Näär AM
通讯作者：
Näär AM

RNA therapeutics: RNAi and antisense mechanisms and clinical applications.

DOI：
10.14304/surya.jpr.v4n7.5
发表时间：
2016-07
期刊：
Postdoc journal : a journal of postdoctoral research and postdoctoral affairs
影响因子：
0
作者：
Chery J
通讯作者：
Chery J