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Principal Investigator: Jiandong Liu
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $662,922
Funding agency: National Heart Lung and Blood Institute
Cardiac fibroblasts (CFs) are the major cardiac cell type responsible for producing extracellular matrix (ECM)
proteins, forming a structural scaffold crucial for supporting cardiac tissue during development and homeostasis.
CFs are also known for their high plasticity, enabling them to swiftly respond to injuries and pathological
conditions. Under such circumstances, CFs are rapidly activated and become transdifferentiated into
myofibroblasts that produce and secrete an excessive amount of ECM components, ultimately leading to fibrotic
scarring that disrupts tissue compliance and accelerates the progression toward heart failure.
The transformation of CFs into myofibroblasts requires wholesale programming of the CF transcriptome. Yet,
in addition to transcriptional regulation, post-transcriptional regulation by RNA-binding proteins (RBPs) has
emerged as a critical regulatory layer for controlling gene expression. RBPs actively regulate every step of mRNA
life cycle, including splicing, stability, and translation. In our preliminary studies, we found that one of RBPs,
Ybx1, was significantly upregulated during CF to myofibroblast conversion and further discovered a potentially
important role of this RBP in myofibroblast formation. Specifically, we found that Tcf21:MerCreMer mediated
ablation of Ybx1 inhibits the transformation of CFs into myofibroblasts and reduces cardiac fibrosis.
While the conversion CFs to myofibroblasts is inherently pathological, the extensive pool and plasticity of
resident CFs has been recently harnessed for cardiac regeneration whereby CFs are reprogrammed into induced
cardiomyocytes (iCMs) by local delivery of three cardiac transcription factors (TFs) - Gata4, Mef2c, Tbx5
(abbreviated as GMT). Building upon our intriguing finding that depletion of Ybx1 attenuates CF to myofibroblast
conversion and reduces cardiac fibrosis, we posed the question whether Ybx1 ablation enhances GMT-mediated
iCM reprogramming. Indeed, our preliminary study indicates that, compared to MGT-mediated iCM
reprogramming, delivery of GMT with Ybx1 depletion enhances iCM induction, further attenuating cardiac fibrosis
and improves heart function following MI.
Combining these two lines of investigation and the corresponding preliminary data, in this proposal we will
leverage our series of unique tools, reagents, and animal models to address our hypothesis that Ybx1 activity
exerts a significant influence on the fate switch involving CFs, specifically the transformation of CFs into
myofibroblasts and the reprogramming of CFs into iCMs, which can be leveraged for reducing fibrotic scarring
and regenerating lost myocardium after MI.
Terms: <21+ years old><ATAC sequencing><ATAC-seq><ATACseq><Abbreviations><Ablation><Acceleration><Accounting><Acute myocardial infarct><Acute myocardial infarction><Address><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Assay for Transposase-Accessible Chromatin using sequencing><Attenuated><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Biology><Body Tissues><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell-Extracellular Matrix><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chromatin><Cicatrix><Cytoplasmic Granules><Cytosol><DNA Binding><DNA Binding Interaction><DNA bound><Data><Death><Development><ECM><Extracellular Matrix><Extracellular Matrix Proteins><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Foundations><GATA binding protein 4><GATA4><GATA4 gene><GATA4 transcription factor><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Transcription Factor Gene><General Transcription Factors><Generations><Goals><Heart Diseases><Heart Injuries><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><High Prevalence><Homeostasis><Induced Cardiomyocytes><Injury><Investigation><Knock-out><Knockout><Knowledge><Life Cycle><Life Cycle Stages><Liquid substance><Mechanics><Mediating><Messenger RNA><Molecular><Morbidity><Morbidity - disease rate><Myocardial Infarct><Myocardial Infarction><Myocardium><Myofibroblast><Natural regeneration><Pathologic><Patients><Phase><Phenotype><Physiological Homeostasis><Play><Polyribosomes><Polysomes><Population><Post-Transcriptional Control><Post-Transcriptional Regulation><Prevalence><RNA Splicing><RNA-Binding Proteins><Reagent><Regeneration><Regenerative capacity><Ribonucleoproteins><Role><Scars><Series><Splicing><Testing><Therapeutic><Tissues><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Translating><Translational Inhibition><Translational Repression><Translations><United States><adulthood><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><attenuate><attenuates><cardiac failure><cardiac fibrosis><cardiac function><cardiac infarct><cardiac injury><cardiac muscle><cardiac regeneration><cardiomyocyte><cardiovascular disorder><cell type><chromatin immunoprecipitation-sequencing><circulatory system><coronary attack><coronary fibrosis><coronary infarct><coronary infarction><deliver mRNA><deliver messenger RNA><delivery system for mRNA><developmental><essays><experiment><experimental research><experimental study><experiments><fibrotic heart><fluid><function of the heart><global gene expression><global transcription profile><granule><heart attack><heart disorder><heart fibrosis><heart function><heart infarct><heart infarction><heart muscle><heart regeneration><icardiomyocytes><improved><in vivo><induced cardiac myocytes><injuries><interest><life course><lipid based nanoparticle><lipid nanoparticle><liquid><mRNA><mRNA delivery><mechanic><mechanical><messenger RNA delivery><model of animal><mortality><myocardial fibrosis><novel><post-transcriptional gene regulation><posttranscriptional control><posttranscriptional regulation><public health relevance><regenerate><regeneration ability><regeneration capacity><scRNA-seq><scaffold><scaffolding><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><tool><transcription factor><transcriptome><translation><translatome>