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Principal Investigator: KATHRYN J MOORE
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $757,945
Funding agency: National Heart Lung and Blood Institute
SUMMARY
In atherosclerotic cardiovascular disease (ASCVD), chronic inflammation is a major risk factor that remains
unaddressed by currently approved therapies. Existing therapies aimed at curbing ASCVD target lipid metabolic
pathways, and many patients continue to be at high risk of cardiovascular disease including myocardial infarction
and stroke. Although inhibition of the pro-inflammatory cytokine interleukin (IL)-1β was shown in the CANTOS
trial to reduce adverse cardiovascular events, the concomitant increased risk of fatal infections hindered its
therapeutic viability. Therefore, narrowing the gap between metabolism and immune cell function to discern the
processes governing inflammation resolution in ASCVD—and why they fail with disease progression—is a major
challenge in the field. To that end, we have identified itaconate, a TCA cycle-derived metabolite produced by the
enzyme cis-aconitate decarboxylase (ACOD1/IRG1), as a driver of inflammation resolution in atherosclerosis.
Itaconate is induced during microbial infection, and harbors anti-microbial and immunomodulatory functions,
including inhibition of the NLRP3-inflammasome, IL-1β secretion and reactive oxygen production. These
inflammatory pathways contribute centrally to atherogenesis, yet the regulation of IRG1 and impact of itaconate
on plaque immune responses has yet to be studied. In this proposal, we aim to (i) determine the metabolic and
immune processes by which the IRG1-itaconate axis curbs inflammatory responses in atherosclerosis and (ii)
investigate the effects of itaconate and its derivatives on atherosclerosis-associated inflammatory responses in
vitro, and iii) test whether the cell-permeable itaconate derivative 4-octyl-itaconate can reduce plaque burden
and instability in mice. Our studies will use novel mouse models to track itaconate abundance in vivo and
innovative 3D human vascular explants to investigate therapeutic modulation of the IRG1-itaconate axis in
ASCVD. Collectively, these investigations will identify novel mechanisms of metabolic control of local and
systemic inflammation during atherosclerosis and provide a foundation for the design of targeted
immunometabolic therapies for ASCVD.
Terms: <1-Propene-1,2,3-tricarboxylic acid><3-D><3-Dimensional><3D><ATAC sequencing><ATAC-seq><ATACseq><Acceleration><Achilleic Acid><Aconitate><Aconitic Acid><Acontic Acid><Active Oxygen><Address><Adonic Acid><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatory Effect><Antioxidants><Apoplexy><Arterial Fatty Streak><Arterial Fatty Streaks><Arterial Intimas><Arteries><Assay for Transposase-Accessible Chromatin using sequencing><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bacterial Infections><Basal Transcription Factor><Basal transcription factor genes><Beta Proprotein Interleukin 1><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><Blood Vessels><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain Vascular Accident><Carboxy-Lyases><Carboxyglutaconic Acid><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Carotid Artery Plaque><Carotid Artery Plaques><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Stress><Cellular Stress Response><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><ChIP Sequencing><ChIP-seq><ChIPseq><Chemotactic Cytokines><Cholesterol><Chronic><Citric Acid Cycle><Citridic Acid><Citridinic Acid><Clinical><Coupled><Cytometry><Data><Decarboxylases><Deposit><Deposition><Disease Progression><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equisetic Acid><Event><Foundations><Fumarate Reductase><General Transcription Factor Gene><General Transcription Factors><Genes><Glycolysis><Glycolysis Inhibition><Goals><HPGF><Heart Vascular><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><Hypercholesteremia><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><Image><Immune><Immune response><Immunes><Immunity><Immunological response><Immunomodulation><Impairment><In Vitro><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Intercrines><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intermediary Metabolism><Intracellular Communication and Signaling><Investigation><Krebs Cycle><LDL><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Lipoproteins><Learning><Lipids><Low Density Lipoprotein Cholesterol><Low-Density Lipoproteins><MGI-2><Macrophage><Marrow Neutrophil><Marrow monocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Metabolic><Metabolic Control><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Modification><Murine><Mus><Myeloid Cells><Myeloid Differentiation-Inducing Protein><Myeloid Progenitor><Myeloid Progenitor Cells><Myeloid Stem Cells><Myocardial Infarct><Myocardial Infarction><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><O element><O2 element><OxLDL><Oxidative Stress><Oxygen><Oxygen Radicals><PBMC><Pathologic Constriction><Pathological Constriction><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Permeability><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pre-Clinical Model><Preclinical Models><Preinterleukin 1 Beta><Pro-Oxidants><Process><Production><Pyrocitric Acid><Reactive Oxygen Species><Regulation><Residual><Residual state><Resolution><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><SIS cytokines><Signal Transduction><Signal Transduction Systems><Signaling><Stenosis><Sterility><Stroke><Subcellular Process><Succinate Dehydrogenase><Succinic Dehydrogenase><Succinic Oxidase><T-Cells><T-Lymphocyte><TCA cycle><Testing><Therapeutic><Therapeutic Uses><Time><Tissues><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Tricarboxylic Acid Cycle><United States><Work><anti-inflammatory effect><anti-microbial><antimicrobial><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><bacteria infection><bacterial disease><beta-Lipoprotein Cholesterol><beta-Lipoproteins><biological signal transduction><brain attack><cardiac infarct><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><carotid plaque><cell stress><cerebral vascular accident><cerebrovascular accident><chemoattractant cytokine><chemokine><chromatin immunoprecipitation-sequencing><circulatory system><coronary attack><coronary infarct><coronary infarction><cytokine><design><designing><driving><epigenetic gene silencing><epigenetic silencing><epigenetically><epigenomics><extracellular><feeding><fumarate hydrogenase><heart attack><heart infarct><heart infarction><high blood cholesterol><high dimensionality><high risk><host response><human RNA sequencing><human RNA-seq><hypercholesterolemia><imaging><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><in vivo Model><innovate><innovation><innovative><interferon beta 2><metabolic phenotype><metabolism measurement><metabolomics><metabonomics><metabotype><microbial><monocyte><mouse model><multiplexed imaging><murine model><myeloid stem and progenitor cell><neutrophil><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ox-LDL><oxidized LDL><oxidized low density lipoprotein><pathway><prevent><preventing><recruit><resolutions><response><scRNA-seq><sensor><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem><sterile><stroked><strokes><systemic inflammation><systemic inflammatory response><three dimensional><thymus derived lymphocyte><transcription factor><treatment strategy><vascular><vulnerable plaque><western diet><western-style diet><western-type diet>