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Principal Investigator: YUQING Eugene CHEN
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2020
Award: $706,887
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <ABC Transport Protein><ABC Transporter Protein><ABC Transporters><ATP-Binding Cassette Transporters><Abscission><Animal Model><Animal Models and Related Studies><Anti-atherogenic><Antiatherogenic><Apo A-1><Apo A-I><Apo A1><Apo AI><Apo-E><ApoA-1><ApoA-I><ApoE><Apolipoprotein A-1><Apolipoprotein A-I><Apolipoprotein A1><Apolipoprotein AI><Apolipoprotein E><Apolipoproteins><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Back><Binding Sites><Biological Function><Biological Markers><Biological Process><Blood Circulation><Blood Plasma><Bloodstream><Body Tissues><Cancers><Cause of Death><Cholesterol><Circulation><Clinical><Clinical Trials><Combining Site><Coronary Disease><Coronary heart disease><Data><Development><Diabetes Mellitus><Dorsum><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drugs><Event><Excision><Extirpation><Feces><Formulation><Frequencies><GWA study><GWAS><Genetic><Goals><HDL><HDL Cholesterol><HDL Cholesterol Lipoproteins><HDL Lipoproteins><Heart failure><Heavy Lipoproteins><Hepatic><High Density Lipoprotein Cholesterol><High Density Lipoproteins><High density lipoprotein><Human><Impairment><Infusion><Infusion procedures><LDL Cholesterol><LDL Cholesterol Lipoproteins><Lipids><Liver><Liver X Receptor><Low Density Lipoprotein Cholesterol><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Membrane><Mice><Mice Mammals><Modern Man><Murine><Mus><Organ><Pathway interactions><Peripheral><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Plasma><Plasma Serum><Prevention><Production><Promoter Regions><Promotor Regions><Property><Reactive Site><Receptor Activation><Regulation><Removal><Reticuloendothelial System, Serum, Plasma><Role><Safety><Surgical Removal><Techniques><Testing><Therapeutic><Therapeutic Index><Time><Tissues><Toxic effect><Toxicities><United States><Up-Regulation><Upregulation><alpha-Lipoprotein Cholesterol><alpha-Lipoproteins><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic heart disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><beta-Lipoprotein Cholesterol><bio-markers><biologic marker><biomarker><cardiac failure><coronary disorder><design><designing><developmental><diabetes><disability><drug/agent><fat metabolism><genetic promoter element><genetic promoter sequence><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><hepatic body system><hepatic organ system><in vivo><knock-down><knockdown><lipid metabolism><loss of function><macrophage><malignancy><membrane structure><model of animal><model organism><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><particle><pathway><prevent><preventing><promoter sequence><resection><reverse cholesterol transport><side effect><site targeted delivery><social role><stool><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><treatment strategy><vulnerable plaque><whole genome association analysis><whole genome association studies><whole genome association study>