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Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates

抗 miR-33 对非人灵长类动物动脉粥样硬化消退和 RCT 的影响

基本信息

批准号：
9181440
负责人：
Ryan Eugene Temel
金额：
$ 72.12万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181440
关键词：
ATP-Binding Cassette Transporters Affect American Antisense Oligonucleotides Aorta Apolipoprotein A-I Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Binding Cercopithecus pygerythrus Characteristics Cholesterol Clinical Treatment Clinical Trials Collagen Complex Coronary artery Coronary heart disease Feces Fiber Foam Cells Future Gene Targeting Genes Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human Implant In Vitro Inflammation Introns Lipids Liver Macaca fascicularis Magnetic Resonance Imaging Measures Mediating MicroRNAs Molecular Sieve Chromatography Monkeys Mus Patients Process Protein Isoforms Proteins Response Elements Risk Risk Factors Role Spectrometry, Mass, Electrospray Ionization Sterols Testing Time Translational Repression fatty acid oxidation gene repression inflammatory marker laser capture microdissection mRNA Transcript Degradation macrophage nonhuman primate novel therapeutic intervention oxidation pre-clinical protective effect reverse cholesterol transport subcutaneous very low density lipoprotein triglyceride

项目摘要

Project Summary The risk of coronary heart disease (CHD), the largest major killer of Americans, is inversely associated with high-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to the role of HDL in reverse cholesterol transport (RCT), a process whereby cholesterol from macrophage foam cells in atherosclerotic plaques is effluxed to HDL, transported to the liver, and excreted in the feces. Despite intense efforts to identify new therapeutic strategies to raise HDL, this has proven to be a challenging endeavor. A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans, two isoforms of this microRNA, miR-33a and miR-33b, are encoded in introns of the sterol response element binding factor (SREBF) 2 and SREBF1 genes, and co-regulate cellular lipid homeostasis with their host genes. Notably, miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterol efflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1 (ABCA1), a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice, which encode only miR-33a, an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic and macrophage ABCA1, HDL-C, RCT, and atherosclerosis regression. However the translational value of the studies in mice was limited by the lack of miR-33b, which is expressed in humans and non-humans primates. To test the effects of inhibiting both miR-33a and b, we recently treated African green monkeys with anti-miR- 33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceride was decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33, the ability of anti-miR-33 to induce the regression of atherosclerosis in a "human-like" species expressing both miR-33a and miR-33b is still unknown. In this application, we propose to determine the effects of anti-miR-33 on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD.

项目总结