KLF14 and Atherosclerosis

KLF14 与动脉粥样硬化

基本信息

批准号：
9333689
负责人：
YUQING Eugene CHEN
金额：
$ 70.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2017-04-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333689
关键词：
ATP-Binding Cassette Transporters Animal Model Antiatherogenic Apolipoprotein A-I Apolipoprotein E Apolipoproteins Arterial Fatty Streak Arteries Atherosclerosis Attenuated Back Binding Sites Biological Markers Biological Process Blood Circulation Cause of Death Cholesterol Clinical Clinical Trials Coronary heart disease Data Development Diabetes Mellitus Dose Drug Delivery Systems Drug Kinetics Drug Targeting Event Excision Formulation Frequencies Genetic Goals Heart failure Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Impairment Infusion procedures LDL Cholesterol Lipoproteins Lipids Liver Liver X Receptor Mediating Membrane Mus Organ Pathway interactions Peripheral Pharmaceutical Preparations Pharmacologic Substance Plasma Prevention Production Promoter Regions Property Receptor Activation Regulation Role Safety Side Techniques Testing Therapeutic Therapeutic Index Time Tissues Toxic effect United States Up-Regulation base design disability genome wide association study in vivo knock-down loss of function macrophage nanoparticle novel novel therapeutics particle prevent reverse cholesterol transport targeted delivery targeted treatment treatment strategy

ATP-Binding Cassette Transporters Animal Model Antiatherogenic Apolipoprotein A-I Apolipoprotein E Apolipoproteins Arterial Fatty Streak Arteries Atherosclerosis Attenuated Back Binding Sites Biological Markers Biological Process Blood Circulation Cause of Death Cholesterol Clinical Clinical Trials Coronary heart disease Data Development Diabetes Mellitus Dose Drug Delivery Systems Drug Kinetics Drug Targeting Event Excision Formulation Frequencies Genetic Goals Heart failure Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Impairment Infusion procedures LDL Cholesterol Lipoproteins Lipids Liver Liver X Receptor Mediating Membrane Mus Organ Pathway interactions Peripheral Pharmaceutical Preparations Pharmacologic Substance Plasma Prevention Production Promoter Regions Property Receptor Activation Regulation Role Safety Side Techniques Testing Therapeutic Therapeutic Index Time Tissues Toxic effect United States Up-Regulation base design disability genome wide association study in vivo knock-down loss of function macrophage nanoparticle novel novel therapeutics particle prevent reverse cholesterol transport targeted delivery targeted treatment treatment strategy

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项目摘要

ABSTRACT Reverse cholesterol transport (RCT) is an important protective mechanism against atherosclerosis, in which plasma high-density lipoprotein cholesterol (HDL-c) interacts with macrophages in arterial wall and shuttles excess of cholesterol back to the liver. In macrophages, the cholesterol efflux activity is controlled by the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Upregulation of ABCA1/ABCG1 in macrophages increases cholesterol efflux activity to HDL particles and decreases atherosclerosis. Kruppel- like factor 14 (KLF14), identified by large genome-wide association studies, is strongly associated with HDL-c level, coronary heart disease (CHD). Our preliminary studies demonstrate that KLF14 increases plasma HDL-c level by modulating hepatic apolipoprotein (apoA-I) production. Intriguingly, we identified that perhexiline, which is clinically used to treat angina and heart failure, is a novel KLF14 activator. Perhexiline-mediated KLF14 activation attenuated atherosclerosis in apoE-deficiency mice. Interestingly, we found that KLF14 regulates cholesterol efflux by upregulation of ABCA1 and ABCG1 in macrophages, which contribute to the availability of cholesterol to apoA-I and HDL. However, perhexiline has sub-optimal pharmaceutical properties such as off-target toxicity, narrow therapeutic index and variable pharmacokinetics. We also demonstrated that synthetic high density lipoprotein (sHDL) nanoparticles could target delivery of drugs to atheroma. These sHDL has been tested in clinical trials at large doses and were found to be safe and have favorable pharmacokinetics. Furthermore, we have developed sHDL-mediated drug delivery platform for atherosclerosis treatment. In this proposal, we will: 1) Determine KLF14 regulates atherosclerotic regression by enhancing cholesterol efflux; 2) Develop sHDL nanoparticles as an efficient atheroma drug delivery system; 3) Determine the ability of sHDL nanoparticles mediated KLF14 activator delivery to promote atherosclerosis regression in vivo. The long-term goal of this project is to understand the function and underlying mechanism of KLF14 in atherosclerosis regression in order to design novel therapeutic strategies for treatment of atherosclerosis.

抽象的反向胆固醇转运（RCT）是针对动脉粥样硬化的重要保护机制，其中血浆高密度脂蛋白胆固醇（HDL-C）与动脉壁和班路的巨噬细胞相互作用胆固醇过量回到肝脏。在巨噬细胞中，胆固醇外排活动受 ATP结合盒（ABC）转运蛋白ABCA1和ABCG1的表达。 ABCA1/ABCG1的上调在巨噬细胞中，将胆固醇外排活性增加对HDL颗粒并减少动脉粥样硬化。 kruppel- 像因子14（KLF14）一样，通过大型基因组关联研究确定，与HDL-C密切相关水平，冠心病（CHD）。我们的初步研究表明，KLF14增加了血浆HDL-C 通过调节肝载脂蛋白（APOA-I）的生产来取得水平。有趣的是，我们确定了Perhexiline，临床用于治疗心绞痛和心力衰竭的是一种新型的KLF14激活剂。 perheciline介导 KLF14激活减弱了APOE缺陷小鼠的动脉粥样硬化。有趣的是，我们发现KLF14 通过巨噬细胞中ABCA1和ABCG1的上调来调节胆固醇外排，这有助于胆固醇可用于ApoA-I和HDL。但是，perhexiline具有亚最佳药物特性例如脱靶毒性，狭窄的治疗指数和可变药代动力学。我们还证明了合成高密度脂蛋白（SHDL）纳米颗粒可以靶向药物递送到动脉粥样硬化。这些SHDL 已在大剂量的临床试验中进行了测试，并被发现安全且具有良好的药代动力学。此外，我们开发了用于动脉粥样硬化治疗的SHDL介导的药物输送平台。在这个提案，我们将：1）确定KLF14通过增强胆固醇外排调节动脉粥样硬化的回归； 2）开发SHDL纳米颗粒作为有效的动脉瘤药物输送系统； 3）确定SHDL的能力纳米颗粒介导了KLF14激活剂的递送，以促进体内动脉粥样硬化的消退。长期该项目的目标是了解动脉粥样硬化中KLF14的功能和潜在机制回归是为了设计用于治疗动脉粥样硬化的新型治疗策略。