PARP9 and PARP14 in atherosclerosis

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Principal Investigator: Masanori  Aikawa
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2019
Award: $602,965
Funding agency: National Heart Lung and Blood Institute

   
DESCRIPTION (provided by applicant): Uncontrolled activation of macrophages promotes various inflammatory diseases. The most devastating diseases linked to macrophage activation include atherosclerosis, a global health burden. To discover novel regulators of macrophage activation as therapeutic targets, we performed global proteomics on IFNγ- triggered M1 and IL-4-induced M2 macrophages. We identified PARP9 and PARP14, ADP-ribosylation enzymes, as key candidates. The functions of these two PARPs have not yet well characterized and their roles in macrophage biology or vascular disease are unknown. Based on our own preliminary findings, this multidisciplinary research project will test the novel hypothesis that PARP9 promotes and PARP14 suppresses macrophage activation. In Specific Aims 1 and 2, we will use mouse models to examine the role of PARP9 and PARP14 in macrophage activation and atherosclerosis. Our pilot studies have demonstrated many new findings on the interplay between PARP9 and PARP14 and their associations with pro-inflammatory STAT1 and anti-inflammatory STAT6. Specific Aim 2 also will use mass spectrometry and systems biology to explore the mechanisms by which the interactions between PARP9 and PARP14 regulate macrophage activation via ribosylation of signaling molecules (e.g., STAT1). Our study will reveal novel mechanisms of macrophage activation and provide a proof of concept that PARP9 and PARP14 can be therapeutic targets for atherosclerosis and its complications. Furthermore, the study will offer new insight into the shared mechanisms for various other inflammatory diseases, leading to exciting future directions and clinical translation.

Terms: <ADP ribosylation><Acute><Acute myocardial infarct><Acute myocardial infarction><Address><Anti-inflammatory><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BAL gene><BAL protein><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Binetrakin><Biology><Blood monocyte><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><Cardiac artery><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Lineage><Cholesterol><Clinic><Collagen><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary artery><D12S1644><Data><Development><Disease><Disorder><Encapsulated><Enzyme Gene><Enzymes><Future><Genes><Goals><Grant><Heart Vascular><Heart artery><Hematopoietic><Human><IFN><IL-4><IL-4-STAT><IL4 Protein><In Vitro><Inflammation><Inflammatory><Injury><Interdisciplinary Research><Interdisciplinary Study><Interferons><Interleukin-4><Interleukin-4 Precursor><LDL Receptors><Lesion><Link><Lipids><Lipoprotein LDL Receptors><Low Density Lipoprotein Receptor><Lymphocyte Stimulatory Factor 1><MCGF-2><Macrophage Activation><Marrow Transplantation><Marrow monocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mast Cell Growth Factor-2><Mechanics><Medicine><Mice><Mice Mammals><Modern Man><Modernization><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Network Analysis><Outcome><PARP Polymerase><PARP9><PARP9 gene><PARS><Pathway Analysis><Patients><Phosphorylation><Pilot Projects><Play><Poly(ADP-ribose) Polymerases><Poly(ADPribose) Polymerase><Population><Preventive><Production><Protein Phosphorylation><Proteomics><R-Series Research Projects><R01 Mechanism><R01 Program><Research Grants><Research Project Grants><Research Projects><Risk><Role><STAT1><STAT1 gene><STAT6><STAT6 gene><STAT6B><STAT6C><STAT91><Short interfering RNA><Signaling Molecule><Small Interfering RNA><Spleen><Spleen Reticuloendothelial System><Systems Biology><T-Cell Growth Factor 2><Testing><Translating><United States><Vascular Diseases><Vascular Disorder><antiinflammatory><arterial lesion><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><blood vessel disorder><cardiac infarct><cardiovascular disorder><circulatory system><clinical translation><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><developmental><experiment><experimental research><experimental study><femoral artery><global health><heart attack><heart infarct><heart infarction><hemopoietic><in vivo><innovate><innovation><innovative><insight><interdisciplinary approach><lipid nanoparticle><macrophage><mechanical><monocyte><mouse model><multidisciplinary approach><murine model><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pilot study><poly ADP polymerase><poly ADP ribose synthetase><pre-clinical><preclinical><public health relevance><siRNA><social role><theories><therapeutic target><vascular dysfunction><vasculopathy><vulnerable plaque>