FKBP5 AND CARDIAC ARRHYTHMOGENESIS

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Na  Li
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $560,545
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY
Atrial fibrillation (AF) is the most frequent arrhythmia. Reduced mRNA expression of FK506-binding protein 5
(FKBP5) was recently discovered in a transcriptomic study with AF patient tissues. However, the functions of
FKBP5 in heart are unknown. Preliminary studies revealed that cardiac specific loss of FKBP5 promotes the AF
development. The long-term goal of this project is to elucidate the function of FKBP5 in the heart and the
underlying arrhythmogenic mechanisms associated with the FKBP5 deficiency, with a view toward developing
new therapeutic strategies to reduce AF risk. We will test the overarching hypothesis that the FKBP5 deficiency
can enhance atrial arrhythmogenesis via a ‘double-hit’ mechanism, i.e. enhancement of Na+/Ca2+ exchanger 1 -
mediated triggered activity in cardiomyocytes, and promotion of fibrotic remodeling due to altered fibroblast
function. We will elucidate the proarrhythmic mechanisms due to cardiomyocyte-specific or fibroblast-specific
loss of FKBP5, respectively. We will also evaluate the anti-AF potential of targeting the FKBP5 pathway. The
proposed studies will unveil the critical role of FKBP5 in regulating cardiac electrophysiology and provide new
insights to molecular mechanisms of AF.

Terms: <Accessory Sinuses><Adenoviridae><Adenoviruses><Adipose tissue><Arrhythmia><Assay><Atrial><Atrial Fibrillation><Auricular Fibrillation><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Body Tissues><CNS Nervous System><Cardiac><Cardiac Arrhythmia><Cardiac Atrium><Cardiac Electrophysiologic Techniques><Cardiac Electrophysiological Diagnostics><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Central Nervous System><Chaperone><Chronic><Crossbreeding><Development><E-stim><Echocardiogram><Echocardiography><Electric Stimulation><Event><FK-506-Binding Protein><FK506 Binding Proteins><FK506 binding protein 5><FKBP><FKBP Rotamase><FKBP51><FKBP54><Fatty Tissue><Fibroblasts><Fibrosis><Gel><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Hybridization><Genetic Transcription><Goals><HSP-90><HSP90><Heart><Heart Arrhythmias><Heart Atrium><Heart Muscle Cells><Heart myocyte><Heat-Shock Proteins 90><Histology><Human><Hypoxia Inducible Factor><Impairment><Incidence><KO mice><Knock-out Mice><Knockout Mice><Left Atrium><Left Ventricles><Left atrial structure><Left ventricular structure><Ligands><Link><LoxP-flanked allele><Maps><Mediating><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Chaperones><Murine><Mus><Myofibroblast><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><Neuraxis><Nuclear Translocation><Null Mouse><Optics><Paranasal Sinuses><Pathogenesis><Pathway interactions><Patients><Pilot Projects><Predisposition><Prevalence><Proteins><Public Health><RNA Expression><Receptor Protein><Recurrence><Recurrent><Risk><Role><Single-Nucleus Sequencing><Sinus><Staining method><Stains><Susceptibility><Tacrolimus Binding Proteins><Testing><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transthoracic Echocardiography><Up-Regulation><Upregulation><Work><adipose><atrium><cardiac electrophysiology><cardiomyocyte><cell type><developmental><electrostimulation><floxed><floxed allele><heart electrophysiology><heart sonography><hsp90 Family><induced Cre><inducible Cre><inhibitor><insight><knock-down><knockdown><mRNA><mRNA Expression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><optical><pathway><pilot study><prevent><preventing><promoter><promotor><receptor><sNuc-Seq><shRNA><short hairpin RNA><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><small hairpin RNA><snRNA sequencing><snRNA-seq><social role><tacrolimus binding protein 5><transcription factor><transcriptomics><white adipose tissue><yellow adipose tissue>