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Principal Investigator: Zhiqiang Lin
Organization: MASONIC MEDICAL RESEARCH LABORATORY, INC
Fiscal Year: 2024
Award: $624,659
Funding agency: National Heart Lung and Blood Institute
Cardiomyocytes (CMs) are building blocks and function units of the heart, and their dysfunction or loss
is the root of heart failure. Similar with other specialized innate immune cells, CMs have their own
innate immune molecular machinery. Ischemic or non-ischemic pathological stress activates CM
innate immune signaling pathways, which stimulate pro-inflammatory cytokine release and reactive
oxygen species (ROS) production. These innate immune responses are beneficial for defending CMs
against pathogen invasion and for tissue repair, but can also cause myocardial damage. The ultimate
goal of this project is to define new molecular mechanisms that regulate CM innate immune
responses, which will shed light on the pathogenesis of pathogen or non-pathogen related
cardiomyopathy. Damage/danger-associated molecular patterns (DAMPs) initiate innate immune
responses by binding to pattern recognition receptors, and one of the best-characterized signaling axis
is TLR4/NF-kB pathway. The Hippo-YAP pathway is crucial for heart development and cardiac
regeneration, and disturbances in Hippo-YAP have been implicated in a range of heart diseases.
IRF2BP2 (interferon regulatory factor 2 binding protein 2) is a transcription co-factor little studied in the
heart. We recently found that YAP regulates CM innate immune responses by blunting TLR4/NF-kB
signaling, and that IRF2BP2 is crucial for restraining TLR4 expression in the heart. In this project, we
will test the hypothesis that YAP and IRF2BP2 are suppressors of CM innate immune responses. We
propose the following two aims. Aim 1. Define the role of YAP in CM innate immune responses. In this
aim, we will determine whether YAP regulation of CM innate immune responses depends on its
transcriptional activity. Additionally, we will develop a novel YAP modRNA delivery system. We
previously showed that transiently activating YAP with intra-myocardial delivered aYAP modRNA
reduced heart injury. However, the in situ delivery method limits aYAP modRNA's clinical application.
Here, we will test the efficacy of CM targeted and nano-particle packaged aYAP modRNA in a murine
cardiac ischemia/reperfusion model. Aim 2. Define the role of IRF2BP2 in CM innate immune
responses. In this aim, we will perform IRF2BP2 gain- and loss-of-function studies to define its role in
CM innate immune responses. Additionally, we will investigate the molecular mechanism of how
IRF2BP2 regulates CM innate immune responses. Using the new Irf2bp2 knock-in mouse line we
have recently generated, we will perform IRF2BP2 ChIP-Seq to identify its direct targets. This proposal
is innovative and significant, as it focuses on dissecting the basic molecular mechanisms that underlie
CMs innate immune responses, and it aims to develop new therapeutic strategies for reducing
myocardial infarction injury.
Terms: <21+ years old><Acceleration><Active Oxygen><Acute myocardial infarct><Acute myocardial infarction><Adult><Adult Human><Binding><Binding Proteins><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac development><Cardiac infarction><Cardiocyte><Cardiomyopathies><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chronic><Complex><Data><Death><Disease><Disorder><Dysfunction><Exposure to><Functional disorder><Gene Transcription><Generalized Growth><Genes><Genetic Transcription><Goals><Growth><HINF-M protein><Heart><Heart Diseases><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Homolog of Drosophila TOLL><IRF-2 protein><Immune><Immune signaling><Immunes><Immunoglobulin Enhancer-Binding Protein><In Situ><Inflammatory><Injury><Innate Immune Response><Innate Immune System><Interferon Regulatory Factor 2><Intracellular Communication and Signaling><Invaded><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><KI mice><Kinases><Knock-in Mouse><Ligand Binding Protein><Ligand Binding Protein Gene><Lipopolysaccharides><MAP kinase kinase kinase 7><MAP3K7><MAP3K7 gene><Maintenance><Mediating><Methods><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Murine><Mus><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardiopathies><Myocarditis><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Oxygen Radicals><Pathogenesis><Pathologic><Pathway interactions><Pattern><Pattern recognition receptor><Phosphotransferase Gene><Phosphotransferases><Physiopathology><Pro-Oxidants><Process><Production><Protein Binding><Proteins><Publishing><RNA Expression><Reactive Oxygen Species><Regulation><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporting><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><System><TAK1><TAK1a><TAK1b><TAK1c><TAK1d><TGF-Beta Activated Kinase 1><TGF-beta-activated kinase 1><TLR4><TLR4 gene><Testing><Tissue Growth><Toll Homologue><Transcription><Transcription Factor NF-kB><Transphosphorylases><adulthood><bacteria pathogen><bacterial pathogen><biological signal transduction><bound protein><cardiac failure><cardiac function><cardiac infarct><cardiac inflammation><cardiac injury><cardiac ischemia><cardiac regeneration><cardiogenesis><cardiomyocyte><cell type><chromatin immunoprecipitation-sequencing><clinical applicability><clinical application><co-repressor><cofactor><corepressor><coronary attack><coronary infarct><coronary infarction><coronary ischemia><cytokine><efficacy testing><function of the heart><gain of function><gene co-repressor><gene corepressor><genetic co-repressor><genetic corepressor><heart attack><heart development><heart disorder><heart formation><heart function><heart infarct><heart infarction><heart ischemia><heart regeneration><histone nuclear factor M><in vitro activity><in vivo><injuries><innate immune pathways><innovate><innovation><innovative><kappa B Enhancer Binding Protein><knockin mice><loss of function><mitogen-activated protein kinase kinase kinase 7><myocardial damage><myocardial ischemia/hypoxia><myocardium disease><myocardium disorder><myocardium ischemia><nano particle><nano-sized particle><nanoparticle><nanosized particle><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><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><nuclear factor kappa beta><ontogeny><overexpress><overexpression><pathogen><pathogenic bacteria><pathophysiology><pathway><reperfusion><restraint><social role><therapeutic target><tissue repair><toll-like receptor 4><transforming growth factor-beta-activated kinase 1>