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Principal Investigator: Sergey Ryzhov
Organization: MAINEHEALTH
Fiscal Year: 2024
Award: $581,578
Funding agency: National Heart Lung and Blood Institute
Our new preliminary data indicate that ErbB3 signaling is essential for the integration of early inflammatory
response with adaptive immunosuppression, thus preventing the activation of cardiac lymphocytes and
protecting the heart against secondary immune cell-mediated tissue damage. We found that ErbB3
upregulates the expression of PD-L1 on myeloid cells in response to their stimulation with inflammatory factors.
Myocardial tissue lymphocytes express high levels of PD-1 that inhibit the activation of T cells upon binding to
PD-L1 on myeloid cells. Reduced level of PD-L1 expression in mice with disrupted ErbB3 signaling is
associated with activation of cytotoxic lymphocytes and myocardial dysfunction in a mouse model of LPS-
driven inflammation. We also found that ErbB3 promotes up-regulation of PD-L1 after ischemia-reperfusion
(I/R) cardiac injury. To better understand the role of ErbB3 in the regulation of the PD-L1/ PD-1 axis and
myocardial protection, we generated novel mouse models with ablation and overexpression of ErbB in myeloid
cells and subsets of myeloid cells, including macrophages, dendritic cells, and Ly6Clow monocytes. In specific
aim 1, we will determine the role of ErbB3 in the regulation of the myocardial PD-L1/PD-1 axis and
immunosuppression during the acute inflammatory response using loss-of-function and gain-of-function mouse
models. In specific aim 2, we will test the hypothesis that ErbB3 downstream signaling promotes synthesis and
prevents degradation of PD-L1 in myeloid cells. In specific aim 3, we will determine the role of lymphocyte
activation and Ly6Clow monocytes in the promotion of fibrosis in remote myocardial areas in mice with disrupted
ErbB3 signaling in myeloid cells.
Terms: <ACT2><AT744.1><Ablation><Acetylcholine Receptor Inducing Activity><Act-2><Activated Lymphocyte><Acute><Area><B7-H1><B7H1><Binding><Blast Transformation><Blastogenesis><Blood monocyte><Body Tissues><Bone-Derived Transforming Growth Factor><Breast Cancer Cell Differentiation Factor P45><CCL20><CCL20 gene><CCL4><CCL4 gene><CD11c><CD274><Cardiac><Cardiac Diseases><Cardiac Disorders><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell surface><Cells><Chemokine (C-C Motif) Ligand 4><Chemokine, CC Motif, Ligand 20><Chemokine, CC Motif, Ligand 4><Chemotactic Cytokines><Co-culture><Cocultivation><Coculture><Coculture Techniques><Data><Dendritic Cells><Development><Exodus 1><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><GFRP1><Gene Expression><Genetic><Growth Factor Response Protein 1><Growth Factor-Inducible Nuclear Protein N10><Heart><Heart Diseases><Heart Hypertrophy><Heart Injuries><Heart Muscle tissue><Heart failure><Homologous Chemotactic Cytokines><Human><ITGAX><ITGAX gene><Immune><Immune Activation 2><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Inflammation><Inflammatory><Inflammatory Response><Innate Immune System><Intercrines><Intracellular Communication and Signaling><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><LARC><Lymphatic cell><Lymphoblast Transformation><Lymphocyte><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><Lymphocytic><MGC9485><MIP1B><MIP1B1><MIP3A><Macrophage><Macrophage Inflammatory Protein 1-Beta><Macrophage Inflammatory Protein 3-Alpha><Maintenance><Marrow monocyte><Mediating><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myeloid Cell Activation><Myeloid Cells><Myocardial><Myocardial Ischemia><Myocardial depression><Myocardial dysfunction><Myocardial tissue><Myocarditis><Myocardium><Mφ><N10><NAK-1><NAK1><NDF Protein><NGFI-B protein><NGFIB><NP10><NR4A1><NR4A1 gene><NRG Proteins><NRG1 Gene Product><NRG1 Protein><NUR77><Neu-Differentiation Factor><Neuregulin 1><Neuregulins><Nr4a1 protein><Nuclear Hormone Receptor TR3><Nuclear Receptor Subfamily 4, Group A, Member 1><Orphan Nuclear Receptor HMR><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Pathway interactions><Patients><Platelet Transforming Growth Factor><Play><Prevention><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteomics><Regulation><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Research><Risk Reduction><Role><SCYA20><SCYA4><SIS cytokines><Sensory And Motor Neuron-Derived Factor><Sensory-and-motor-derived factor><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A4><Small Inducible Cytokine Subfamily A, Member 20><Steroid Receptor TR3><System><T-Cell Activation><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TR3><Testing><Tissues><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Up-Regulation><Upregulation><Veiled Cells><activate T cells><biological signal transduction><cardiac dysfunction><cardiac failure><cardiac fibrosis><cardiac function><cardiac hypertrophy><cardiac inflammation><cardiac injury><cardiac ischemia><cardiac muscle><chemoattractant cytokine><chemokine><coronary fibrosis><coronary ischemia><cytotoxic><developmental><experiment><experimental research><experimental study><experiments><fibrotic heart><function of the heart><gain of function><heart cell><heart disorder><heart dysfunction><heart fibrosis><heart function><heart ischemia><heart muscle><host response><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><injured><injury to the myocardium><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><loss of function><lymph cell><lymphocyte trafficking><mRNA Expression><monocyte><mouse model><murine model><myocardial damage><myocardial fibrosis><myocardial injury><myocardial ischemia/hypoxia><myocardium ischemia><nerve growth factor-inducible B><neutralizing antibody><novel><orphan nuclear receptor NGFI-B><orphan nuclear receptor NR4A1><overexpress><overexpression><paracrine><pathway><periostin><pressure><prevent><preventing><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><programs><protein death-ligand 1><protein expression><public health relevance><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><reperfusion><response><risk-reducing><sle2><social role><systemic lupus erythematosus susceptibility 2>