Project Grant R01HL170060

BIOMIMETIC NANOMATERIALS FOR THE IMMUNOMODULATION OF THE CARDIOSPLENIC AXIS POST-MYOCARDIAL INFARCTION - PROJECT SUMMARY/ABSTRACT THE HEALING RESPONSE WITHIN THE MYOCARDIUM AFTER A MYOCARDIAL INFARCTION (MI) IS COMPLEX AND INVOLVES BOTH TEMPORAL AND REGIONAL CHANGES INCLUDING INFLAMMATION, CARDIAC SCAR FORMATION, AND TISSUE REMODELING. WITHIN MINUTES FOLLOWING ISCHEMIC INJURY NEUTROPHILS AND MONOCYTES ARE RECRUITED TO THE DAMAGED HEART. AS THE MONOCYTES ARE ACTIVATED, ENTER THE MYOCARDIUM AND ARE STIMULATED BY THE CARDIAC ENVIRONMENT, THEY MATURE INTO A DIVERSE POPULATION OF MACROPHAGES. IN THE FIRST DAYS POST-MI, INFLAMMATORY MONOCYTES AND MACROPHAGES FACILITATE THE REMOVAL OF NECROTIC TISSUE BY SECRETING PROTEASES AND INFLAMMATORY ENZYMES AND CYTOKINES. AS HEALING PROGRESSES, THE REPARATIVE LESS INFLAMMATORY MACROPHAGES BEGIN TO DOMINATE, SECRETING ANTI- INFLAMMATORY CYTOKINES AND COMMUNICATING WITH MYOFIBROBLASTS, ENDOTHELIAL CELLS, PARENCHYMAL AND LOCAL PROGENITOR CELLS TO HELP COORDINATE REMODELING AND REPAIR OF THE DAMAGED TISSUE. OVER THE LAST DECADE THE IMPORTANCE OF THE SPLEEN HAS BEEN HIGHLIGHTED AS A RESERVOIR FOR THE MAJORITY OF MONOCYTES TRAFFICKING TO THE HEART IN RESPONSE TO ISCHEMIC DAMAGE. UPON INFARCTION, INCREASED ANGIOTENSIN II LEVELS PROMOTE THE MIGRATION OF MONOCYTES FROM THE SPLEEN TO THE HEART WHERE THEY DIFFERENTIATE INTO MACROPHAGES AND PARTAKE IN THE INFLAMMATORY PHASE OF THE INSULT. FURTHER, THE SPLEEN IS A MAJOR SITE OF MONOCYTE PROLIFERATION POST MI AND CONTRIBUTES SIGNIFICATE NUMBERS OR MONOCYTES THROUGHOUT THE DURATION OF ACUTE INFLAMMATION. DAYS AFTER THE INITIAL INJURY, THE PHENOTYPE OF MONOCYTES RECRUITED FROM THE SPLEEN CHANGES TO ONE THAT IS REPARATIVE, DIFFERENTIATING INTO MACROPHAGES WHICH SUPPRESS INFLAMMATION, INDUCING MATRIX DEPOSITION AND ANGIOGENESIS. WE HAVE DEMONSTRATED THAT THE SYSTEMIC INHIBITION OF HDACS RESULTS IN MYOCARDIAL PRESERVATION AFTER MI, AND MORE RECENTLY SHOWN THAT THE DELIVERY OF THIS PAN-HDAC INHIBITOR SPECIFICALLY TO THE SPLEEN IS CAPABLE OF PRODUCING A COMPARABLE THERAPEUTIC EFFECT, YET AT A 33-FOLD REDUCED DOSE. THIS PROPOSAL THUS AIMS TO UNEARTH THE MECHANISMS RESPONSIBLE FOR THIS OBSERVED EFFICACY, BOTH WITHIN THE SPLEEN AND THE HEART. AS WELL, THE ADVANCED NANOMATERIALS WITH ENHANCED SPLENIC RETENTION WILL ALSO BE UTILIZED TO DISSECT THE RELEVANT CONTRIBUTIONS OF EACH HDAC TO THE THERAPEUTIC EFFECT, ULTIMATELY RESULTING IN AN OPTIMIZED THERAPEUTIC REGIME.