Project Grant R01HL171135

KMT2A/MLL1 REGULATION OF ENDOTHELIAL ACTIVATION - PROJECT SUMMARY / ABSTRACT EXCESSIVE ENDOTHELIAL INFLAMMATION, 'ENDOTHELIITIS,' IS A HALLMARK PATHOLOGIC FEATURE OF SEVERE SARS-COV2 INFECTION. THE SEQUALAE OF ENDOTHELIITIS, SUCH AS MICROTHROMBOSIS AND TISSUE HYPERPERMEABILITY, CULMINATE IN A MALADAPTIVE HOST RESPONSE CHARACTERIZED BY INTERSTITIAL EDEMA, TISSUE DAMAGE, AND END ORGAN DYSFUNCTION. DESPITE ADVANCES IN VACCINES AND ANTIVIRAL TREATMENTS, THE MOST SEVERELY ILL PATIENTS SUFFERING FROM SARS-COV2 RELATED ENDOTHELIITIS HAVE AN ELEVATED RISK OF MORTALITY. THERE ARE CURRENTLY NEITHER SPECIFIC MEDICATIONS AVAILABLE TO TREAT NOR TO PREVENT ENDOTHELIITIS. CURRENT THERAPIES FOR SEVERE SARS-COV-2 INFECTION ARE LIMITED TO NON-SPECIFIC STEROIDS, IMMUNOMODULATORS AND ANTICOAGULANTS: ALL ARE LIMITED IN CLINICAL USE DUE TO SIGNIFICANT RISK PROFILE FROM OFF-TARGET EFFECTS. THUS, A CRITICAL NEED EXISTS FOR UNDERSTANDING SPECIFIC REGULATORS OF THE DYSFUNCTIONAL ENDOTHELIAL RESPONSE FOR DEVELOPMENT OF TARGETED THERAPIES. UTILIZING HUMAN SARS-COV2 SPECIMENS AND MULTIPLE MURINE CORONAVIRUS MODELS, WE IDENTIFY A NOVEL ROLE FOR HISTONE METHYLTRANSFERASE MLL1 IN REGULATING GENE EXPRESSION CENTRAL TO THE ENDOTHELIITIS RESPONSE: CELLULAR ADHESION MOLECULES (CAMS) AND PRO-COAGULANT MEDIATORS (PCMS). THROUGH A SERIES OF EXPERIMENTS, WE HAVE IDENTIFIED SPECIFIC SIGNAL TRANSDUCER AND ACTIVATORS OF TRANSCRIPTION (STATS) AS IMPORTANT DRIVERS OF VIRAL-INDUCED MLL1 EXPRESSION AND IL-1 RECEPTOR-ASSOCIATED KINASES (IRAKS) AS KEY REGULATORS OF MLL1 DEGRADATION. HENCE, WE IDENTIFIED THAT THE IMBALANCE OF STAT-MEDIATED EXPRESSION AND IRAK-MEDIATED DEGRADATION OF MLL1 AUGMENTS VIRAL ENDOTHELIITIS. THESE RESULTS HAVE LED TO OUR HYPOTHESIS THAT ENDOTHELIITIS GENE EXPRESSION IN RESPONSE TO CORONAVIRUS IS MECHANISTICALLY DRIVEN BY THE STAT-MLL1-IRAK PATHWAY AND PROMOTES OVERT ENDOTHELIAL ACTIVATION, MICROTHROMBOSIS, AND END-ORGAN DAMAGE. WE FURTHER POSTULATE THAT ENDOTHELIAL HOMEOSTASIS MAY BE RESTORED VIA NANOPARTICLE ENCAPSULATED MLL1 INHIBITOR TARGETED TO THE ENDOTHELIAL CELLS, RESULTING IN ATTENUATION OF VIRAL-INDUCED ENDOTHELIITIS. THIS HYPOTHESIS WILL BE INVESTIGATED VIA THE FOLLOWING SPECIFIC AIMS: AIM 1: TO DETERMINE THE MECHANISM(S) BY WHICH MLL1 TARGETS ENDOTHELIAL CAMS AND PCMS PROMOTOR REGIONS. AIM 2: TO DETERMINE THE ROLE OF STAT-1/3 IN ENDOTHELIAL MLL1 INDUCTION AND IRAK4 IN MLL1 DEGRADATION. AIM 3: TO DETERMINE FUNCTIONAL IMPACT OF ENDOTHELIAL SPECIFIC MLL1 INHIBITION ON EC ADHESIVE CHARACTERISTICS AND THROMBOTIC PROPENSITY IN VIVO. COMPLETION OF THESE AIMS WILL INCREASE OUR MECHANISTIC UNDERSTANDING OF ENDOTHELIAL MLL1 AS MASTER REGULATOR OF ENDOTHELIITIS-RELATED GENES IN AN INFECTIOUS CONTEXT. THE RESULTS FROM THIS PROPOSAL WILL DEFINE FOR THE FIRST TIME THE ABILITY OF AN ENDOTHELIAL- TARGETED THERAPY TO INHIBIT THE PATHOLOGIC FEATURES OF SEVERE SARS-COV2 INFECTION.