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ROLES OF HISTONE LYSINE DEMETHYLASES KDM5A AND KDM5B IN THE PATHOGENESIS OF HEART FAILURE - HEART FAILURE (HF) IS A MULTI-FACETED SYNDROME CHARACTERIZED BY SIGNIFICANT MORBIDITY AND MORTALITY. HEREDITARY CARDIOMYOPATHIES ARE COMMON CAUSES OF HF - NOTABLE AMONG THEM BEING MUTATIONS IN LAMIN GENE THAT CAUSE PROGRESSIVE DILATED CARDIOMYOPATHY AND SEVERE HF (LMNA-DCM). IRRESPECTIVE OF THE ETIOLOGY, THE DEVELOPMENT AND PROGRESSION OF HF IS ASSOCIATED WITH SEVERAL FEATURES, INCLUDING MITOCHONDRIAL DYSFUNCTION, ALTERATIONS IN SARCOMERE COMPOSITION, AND METABOLIC DYSREGULATION. THESE PATHOLOGICAL CHANGES ARE PRECEDED AND/OR ACCOMPANIED BY CHANGES IN GENE EXPRESSION DRIVEN BY EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS. IMPORTANCE OF EPIGENETIC REGULATORS ARE BEGINNING TO EMERGE IN HF. HOWEVER, THE ROLES OF HISTONE DEMETHYLASES, ESPECIALLY H3K4 DEMETHYLASES, DESPITE THEIR CRITICAL ROLE IN GENE EXPRESSION REGULATION, REMAIN LARGELY UNKNOWN IN HF. THE MAJOR REGULATORS OF THE H3K4 METHYLATION STATE ARE KDM5 FAMILY OF DEMETHYLASES, WHICH SUPPRESS GENE EXPRESSION BY ELIMINATING THE METHYL MOIETIES FROM H3K4 (H3K4ME3→H3K4). THE PROPOSED RESEARCH IS MOTIVATED BY OUR RECENT FINDINGS OF KDM5A AND KDM5B DYSREGULATION IN HUMAN HF AND MOUSE MODELS OF LMNA-DCM, AS WELL AS PRELIMINARY RESULTS DEMONSTRATING ACTIVATION OF KDM5A AND KDM5B IN THE HEART OF MICE SUBJECTED TO TRANSVERSE AORTIC CONSTRICTION (TAC). FURTHERMORE, OUR PRELIMINARY DATA ALSO SHOW THAT DELETION OF KDM5A IMPROVED CARDIAC FUNCTION AND INCREASED SURVIVAL IN AN LMNA-DCM MOUSE MODEL (MYH6- CRE: LMNAF/F), AND SUPPRESSION OF KDM5 IN VITRO AND DELETION OF KDM5A IN LMNA-DCM MOUSE MODEL INDUCED EXPRESSION OF ITS TARGET GENES, A SUBSET ARE INVOLVED IN OXIDATIVE PHOSPHORYLATION METABOLISM AND SARCOMERE FORMATION. THE DATA SUGGEST BROAD PATHOGENIC ROLE OF KDM5 IN HF. HOWEVER, NEITHER THE INDIVIDUAL NOR COMBINED ACTIONS OF KDM5A AND KDM5B, AS WELL AS THEIR PRECISE MOLECULAR TARGETS IN CM IN HF, ARE KNOWN. AS A RESULT, THE GOAL OF THIS PROJECT IS TO DETERMINE THE PATHOGENIC ROLES AND MOLECULAR TARGETS OF KDM5A AND B IN LMNA- DCM AND HF. AIM 1 WILL INVESTIGATE THE MECHANISM(S) OF PHENOTYPIC RESCUE FOLLOWING KDM5A AND KDM5B DELETION IN A MOUSE MODEL OF LMNA-DCM. AIM 2 BROADENS THE SCOPE OF THE INVESTIGATION BY DETERMINING THE PATHOGENIC ROLES AND MOLECULAR MECHANISMS OF KDM5A AND KDM5B IN PRESSURE-OVERLOAD-INDUCED HF. IN AIM3, WE WILL INVESTIGATE CAUSE AND EFFECT BY RE-EXPRESSING KDM5A AND KDM5B IN CM USING DOX-INDUCIBLE BIGENIC MICE, AND DETERMINING ITS SUFFICIENCY TO INDUCE CARDIAC DYSFUNCTION AND HF, AS WELL AS THEIR REVERSAL WHEN GENE IS SWITCHED OFF BY DOX WITHDRAWAL. THE MOLECULAR MECHANISMS BEHIND PHENOTYPIC CHANGES WILL BE INVESTIGATED UTILIZING RNA- SEQ AND CUT & RUN ASSAYS IN CM, WITH THE LATTER MAPPING GENOMIC OCCUPANCY OF KDM5A, KDM5B, AND H3K4ME3. THE EFFECT OF KDM5A AND B ON GENOME-WIDE CHROMATIN ACCESSIBILITY IN CM, WHICH LEADS TO GENE DYSREGULATION, WILL BE INVESTIGATED USING ATAC-SEQ. AT THE CONCLUSION OF THE STUDY, WE WILL ASCERTAIN THE PATHOGENIC ROLES OF KDM5A AND B AND THEIR MOLECULAR MECHANISMS. THE FINDINGS MAY PAVE THE WAY FOR THE FUTURE DEVELOPMENT OF SPECIFIC TREATMENT FOR TARGETING KDM5A AND KDM5B PROTEINS IN DCM AND HF.
$601.6k 7/15/24