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Principal Investigator: Hong Chen
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $770,203
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Atherosclerosis is the leading cause of life-threatening coronary heart disease, ischemic stroke, and peripheral
arterial disease in the United States. Notably, dyslipidemia remains a major risk factor despite effective lipid-
lowering therapies and prevention programs. This is, in part, due to overwhelming arterial inflammation that
drives the transition from a stable to vulnerable and rupture-prone atheroma. The lack of effective therapies to
lower circulating cholesterol while forcefully curbing arterial inflammation during atheroma progression
presents an opportunity to develop innovative, new medicines for this devastating disease. Understanding the
causative molecular mechanisms responsible for dyslipidemia and arterial inflammation should provide for the
rapid development of more potent therapeutic approaches. Our long-term goal is to uncover molecular
mechanisms underlying the pathophysiology and unearth fresh potential therapeutic targets. Much of our
earlier research has centered on examining the role of epsin endocytic adaptor proteins in endothelial cells and
macrophages to regulate progression of atherogenesis. We have demonstrated that epsins 1 and 2 are
upregulated in atherosclerotic plaques in mouse models of atherosclerosis and human atherosclerotic lesions.
Consequently, deletion of epsins in the endothelium and macrophages resulted in marked attenuation of
atherogenesis. Mechanistically, we showed that epsins escalate arterial inflammation by expressing adhesion
molecules, enhancing monocyte recruitment, and hindering efferocytosis. More recently, we created a liver-
specific deficiency of epsins in an atherosclerotic mouse model and found that atherogenesis was greatly
inhibited and accompanied with diminished blood cholesterol levels and triglyceride levels. Therefore, targeting
epsins, their binding partners, and downstream targets represents an attractive therapeutic approach to
resolve both chronic vascular inflammation and dyslipidemia associated with atheroma development. In this
new application, our proposal builds on compelling evidence that epsins contribute to hyperlipidemia by
enhancing sterol regulatory element binding protein (SREBP) transcriptional activity to promote cholesterol
synthesis as well as increasing low density lipoprotein receptor (LDLR) degradation to perturb oxidized lipid
clearance in the liver. By targeting liver epsins using nanoparticle-encapsulated siRNAs, we hope to design a
novel therapeutic strategy to impede dyslipidemia in atherosclerosis. We will investigate the following Specific
Aims using unique mutant mice, in vitro models, and novel reagents: 1) to determine the molecular
mechanisms by which liver epsins regulate SREBPs in atherosclerosis, 2) to determine the molecular
mechanisms of liver epsin-mediated downregulation of LDLR in atherosclerosis, and 3) to determine the
therapeutic potential of targeting liver epsins for atheroma resolution. If fruitful, our findings will uncover original
roles for liver epsins in fueling hyperlipidemia in atherosclerosis, offer a new class of therapeutic strategies for
treating this disease, and inaugurate a paradigm shift in research relevant to fighting cardiovascular disease.
Terms: <3-hydroxy-3-methylglutaryl-CoA><3-hydroxy-3-methylglutaryl-coenzyme A><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Adhesion Molecule><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Apoplexy><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Blood><Blood Reticuloendothelial System><Blood monocyte><Brain Vascular Accident><Cardiac infarction><Cardiovascular Diseases><Cause of Death><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Communication and Signaling><Cell Signaling><Cellular injury><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Cholesterol><Chronic><Complement><Complement Proteins><Coronary Disease><Coronary heart disease><Death><Dehydrogenases><Deposit><Deposition><Development><Diet><Disease><Disorder><Down-Regulation><Dysfunction><Dyslipidemias><Encapsulated><Endothelial Cells><Endothelium><Event><FKHR><FOXO1><FOXO1A><FOXO1A gene><Foam Cells><Forkhead Box O1A><Forkhead in Rhabdomyosarcoma><Fortification><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genetic Transcription><Goals><Growth><HMG-CoA><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Hyperlipemia><Hyperlipidemia><Incidence><Inflammation><Intracellular Communication and Signaling><Ischemic Stroke><Knowledge><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Receptors><Lesion><Life><Life Style><Lifestyle><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><Lipoprotein LDL Receptors><Liver><Liver Cells><Low Density Lipoprotein Cholesterol><Low Density Lipoprotein Receptor><Macrophage><Marrow monocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Medicine><Mice><Mice Mammals><Mission><Modeling><Modern Man><Modernization><Molecular><Molecular Interaction><Murine><Mus><Mutant Strains Mice><Myelogenous><Myeloid><Myocardial Infarct><Myocardial Infarction><Mφ><NIH><National Institutes of Health><Nuclear Import><OxLDL><Oxidoreductase><Oxidoreductase Gene><Patients><Peripheral arterial disease><Persons><Physiopathology><Predisposition><Prevention program><Production><Protein Binding><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reagent><Reductases><Regulatory Element><Research><Resolution><Risk Factors><Role><Rupture><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Interfering RNA><Sterols><Stroke><Subendothelial Layer><Susceptibility><Testing><Therapeutic><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Triacylglycerol><Triglycerides><Ubiquitilation><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitination><Ubiquitinoylation><United States><United States National Institutes of Health><Work><adapter protein><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic heart disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><attenuation><beta-Lipoprotein Cholesterol><biological signal transduction><blood lipid><bound protein><brain attack><cardiac infarct><cardiovascular disorder><cell adhesion protein><cell damage><cell injury><cellular damage><cerebral vascular accident><cerebrovascular accident><complementation><coronary attack><coronary disorder><coronary infarct><coronary infarction><damage to cells><design><designing><developmental><diets><effective therapy><effective treatment><epsin><epsin 1><fighting><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><hydroxymethylglutaryl-CoA><in vitro Model><inhibitor><injury to cells><innovate><innovation><innovative><monocyte><mouse model><mouse mutant><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><ox-LDL><oxidized LDL><oxidized lipid><oxidized low density lipoprotein><pathophysiology><peripheral artery disease><prevent><preventing><protective effect><protein activation><protein expression><recruit><resolutions><siRNA><social role><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic evaluation><therapeutic target><therapeutic testing><transcription factor><transcriptome sequencing><transcriptomic sequencing><translational opportunities><translational potential><ubiquination><ubiquitin conjugation><ubiquitin ligase><vascular inflammation><vulnerable plaque><western diet><western-style diet><western-type diet>