KLF14 and Atherosclerosis
KLF14 与动脉粥样硬化
基本信息
- 批准号:9333689
- 负责人:
- 金额:$ 70.24万
- 依托单位:
- 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:
- 关键词:ATP-Binding Cassette TransportersAnimal ModelAntiatherogenicApolipoprotein A-IApolipoprotein EApolipoproteinsArterial Fatty StreakArteriesAtherosclerosisAttenuatedBackBinding SitesBiological MarkersBiological ProcessBlood CirculationCause of DeathCholesterolClinicalClinical TrialsCoronary heart diseaseDataDevelopmentDiabetes MellitusDoseDrug Delivery SystemsDrug KineticsDrug TargetingEventExcisionFormulationFrequenciesGeneticGoalsHeart failureHepaticHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHumanImpairmentInfusion proceduresLDL Cholesterol LipoproteinsLipidsLiverLiver X ReceptorMediatingMembraneMusOrganPathway interactionsPeripheralPharmaceutical PreparationsPharmacologic SubstancePlasmaPreventionProductionPromoter RegionsPropertyReceptor ActivationRegulationRoleSafetySideTechniquesTestingTherapeuticTherapeutic IndexTimeTissuesToxic effectUnited StatesUp-Regulationbasedesigndisabilitygenome wide association studyin vivoknock-downloss of functionmacrophagenanoparticlenovelnovel therapeuticsparticlepreventreverse cholesterol transporttargeted deliverytargeted treatmenttreatment strategy
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
胆固醇反向转运(RCT)是对抗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) 与动脉壁和穿梭细胞中的巨噬细胞相互作用
多余的胆固醇回到肝脏。在巨噬细胞中,胆固醇流出活性由
ATP 结合盒 (ABC) 转运蛋白 ABCA1 和 ABCG1 的表达。 ABCA1/ABCG1 上调
巨噬细胞中的胆固醇增加高密度脂蛋白颗粒的流出活性并减少动脉粥样硬化。克鲁佩尔-
大型全基因组关联研究发现,因子 14 (KLF14) 与 HDL-c 密切相关
水平,冠心病(CHD)。我们的初步研究表明 KLF14 增加血浆 HDL-c
通过调节肝载脂蛋白(apoA-I)的产生来降低水平。有趣的是,我们发现哌克西林,
临床上用于治疗心绞痛和心力衰竭,是一种新型的KLF14激活剂。哌克昔林介导
KLF14 激活可减轻 apoE 缺陷小鼠的动脉粥样硬化。有趣的是,我们发现 KLF14
通过上调巨噬细胞中的 ABCA1 和 ABCG1 来调节胆固醇流出,这有助于
胆固醇对 apoA-I 和 HDL 的可用性。然而,哌可昔林的药物特性不佳
例如脱靶毒性、狭窄的治疗指数和可变的药代动力学。我们还证明了
合成高密度脂蛋白(sHDL)纳米颗粒可以将药物靶向输送至动脉粥样硬化斑块。这些sHDL
已在大剂量的临床试验中进行测试,结果显示安全且具有良好的药代动力学。
此外,我们还开发了用于动脉粥样硬化治疗的 sHDL 介导的药物递送平台。在这个
根据建议,我们将: 1) 确定 KLF14 通过增强胆固醇流出来调节动脉粥样硬化的消退; 2)
开发 sHDL 纳米粒子作为有效的动脉粥样硬化药物输送系统; 3)确定sHDL的能力
纳米颗粒介导 KLF14 激活剂递送以促进体内动脉粥样硬化消退。长期来看
该项目的目标是了解KLF14在动脉粥样硬化中的功能和潜在机制
回归以设计治疗动脉粥样硬化的新治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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YUQING Eugene CHEN其他文献
YUQING Eugene CHEN的其他文献
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{{ truncateString('YUQING Eugene CHEN', 18)}}的其他基金
Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
- 批准号:
10580855 - 财政年份:2022
- 资助金额:
$ 70.24万 - 项目类别:
Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
- 批准号:
10462357 - 财政年份:2022
- 资助金额:
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Development of gene editing based therapy for cardiovascular diseases
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10313701 - 财政年份:2021
- 资助金额:
$ 70.24万 - 项目类别:
Development of gene editing based therapy for cardiovascular diseases
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- 批准号:
10441548 - 财政年份:2021
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$ 70.24万 - 项目类别:
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- 批准号:
10451711 - 财政年份:2019
- 资助金额:
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