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Principal Investigator: Ge Tao
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $373,750
Funding agency: National Heart Lung and Blood Institute
Project Summary
This proposal describes a five-year program to investigate the roles of paired-like homeodomain 2 (Pitx2)
signaling during cellular injury response and fibrotic scar formation after myocardial infarction (MI). MI accounts
for millions of deaths worldwide annually. Therefore, developing an effective regenerative therapy is one of the
major goals of modern cardiovascular biology. Pitx2, when overexpressed in cardiomyocytes, is capable of
partially repairing myocardium in a mouse MI model. Pitx2 function is induced and promoted by the upstream
nuclear factor erythroid 2 like 2 (Nrf2), a known regulator of redox balance. Unlike most of the regeneration-
promoting factors that induce cell cycle reentry in cardiomyocytes, the Pitx2 signaling only has a mild effect on
cardiomyocyte proliferation. Instead, Pitx2 regulates the expression of antioxidant scavengers and components
of respiratory chain, both are critical for cell survival and homeostasis. Our Preliminary studies also suggest a
role of Pitx2 in myofibroblast activity and fibrosis formation. Therefore, targeting Pitx2 for therapeutics provides
alternative strategies which focus on cell survival and removing fibrosis. However, an in-depth study of Pitx2 is
needed for designing an efficient targeting strategy. The Specific Aim 1 will test the hypothesis that
overexpression of Pitx2 promotes the degradation of Nrf2 by inducing the expression of E3 ubiquitin-protein
ligase Rbx1. This proposed negative feedback loop may promote the degradation of Nrf2, a key factor for the
nuclear translocation and activity of Pitx2. We aim to explain why Pitx2 overexpression in myocardium can only
partially repair the myocardium after MI. Transgenic mice with modified Pitx2 and/or Rbx1 expression will be
subjected to MI to examine the hypothesis. We will also test an improved therapeutic strategy by
overexpressing Pitx2 and Nrf2 simultaneously in infarcted cardiomyocytes. The Specific Aim 2 will focus on the
downstream effects of Pitx2 signaling and test the hypothesis that Pitx2 activity in cardiomyocytes inhibits the
transition of cardiac fibroblasts to myofibroblasts after MI. Preliminary data suggest that Pitx2 signaling in
cardiomyocyte can affect myofibroblast activity. We proposed an interaction between cardiomyocytes and
cardiac fibroblasts, coordinated by Pitx2, that can regulate fibrosis formation after MI. Mouse models with
modified Pitx2 expression and in vitro primary cell cultures will be used to examine how cardiomyocyte-derived
signaling can regulate fibroblast-to-myofibroblast transition, myofibroblast migration, and ECM deposition.
Terms: <Active Oxygen><Affect><Alleles><Allelomorphs><Antioxidants><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Biology><Body Tissues><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Nucleus><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cellular injury><Cessation of life><Cicatrix><Compensation><Complex><Culturing, in vitro Vertebrate, Primary><Cytoplasm><Data><Death><Deposit><Deposition><Down-Regulation><E3 Ligase><E3 Ubiquitin Ligase><ECM><Electron Transport><Equilibrium><Extracellular Matrix><Feedback><Fibroblasts><Fibrosis><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Goals><Heart><Heart Injuries><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><Homeo Domain><Homeostasis><In Vitro><Infarction><Injury><Intracellular Communication and Signaling><Left><Left Ventricles><Left ventricular structure><Mice><Mice Mammals><Modeling><Modernization><Molecular Interaction><Murine><Mus><Myocardial><Myocardial Infarct><Myocardial Infarction><Myocardium><Myofibroblast><NF-E2 protein><NF-E2 transcription factor><NFE2 protein><Natural regeneration><Nuclear Translocation><Nucleus><Operative Procedures><Operative Surgical Procedures><Oxidation-Reduction><Oxidative Stress><Oxygen Radicals><Pathway interactions><Physiological Homeostasis><Primary Cell Cultures><Pro-Oxidants><Proliferating><Proteins><RNA Expression><Reactive Oxygen Species><Redox><Regeneration><Reporting><Respiratory Chain><Role><Scars><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Ventricle Remodeling><Ventricular><Ventricular Cardiac Remodeling><Ventricular Myocardial Remodeling><Ventricular Remodeling><Work><balance><balance function><biological signal transduction><cardiac failure><cardiac infarct><cardiac injury><cardiac muscle><cardiac regeneration><cardiomyocyte><cell damage><cell injury><cellular damage><circulatory system><coronary attack><coronary infarct><coronary infarction><damage to cells><design><designing><electron transfer><global gene expression><global transcription profile><heart attack><heart infarct><heart infarction><heart muscle><heart regeneration><homeodomain><improved><infarct><injuries><injury response><injury to cells><migration><mouse model><murine model><myocardial remodeling><nuclear factor-erythroid 2><overexpress><overexpression><oxidation reduction reaction><pathway><programs><regenerate><regeneration based therapy><regeneration therapy><regenerative><regenerative therapeutics><regenerative therapy><repair><repaired><response to injury><single cell next generation sequencing><single cell sequencing><social role><surgery><transcription factor><transcriptome><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase>