Project Grant R43HL160338

YOUNG, LINDON H - PROJECT SUMMARY WE ARE SEEKING FUNDING TO TEST THE CARDIO PROTECTIVE EFFECTS OF A NOVEL NEW PROTEIN KINASE C EPSILON (PKCE) INHIBITOR (YT-002) AND A NOVEL PROTEIN KINASE C BETA II (PKCSSII) INHIBITOR (YT-004) IN THE SETTING OF PORCINE MYOCARDIAL ISCHEMIA REPERFUSION (I/R) IN VIVO WHEN GIVEN AT THE BEGINNING OF REPERFUSION. THERE CURRENTLY IS NO APPROVED PHARMACOLOGICAL TREATMENT/PREVENTATIVE FOR THE I/R INJURY. WE ARE FULLY AWARE OF THE PAST FAILURES IN THIS AREA. LITERALLY ALL PREVIOUS ATTEMPTS HAVE TAKEN THE OXYGEN FREE RADICAL SCAVENGING APPROACH. WE BELIEVE THIS UNDERLIES, AT LEAST IN PART, THE REASON THERE HAVE BEEN NO SUCCESSFUL PHARMACOLOGICAL THERAPEUTICS FOR CARDIAC I/R INJURY TO DATE. ONCE REACTIVE OXYGEN SPECIES ARE GENERATED THE DAMAGE IS IMMEDIATE AND SCAVENGING IS INEFFECTIVE. OUR APPROACH - NEVER BEEN TRIED BEFORE - IS TO INHIBIT THE GENERATION OF REACTIVE OXYGEN SPECIES THUS PREVENTING THEIR DAMAGE DURING REPERFUSION. INTERVIEWS WE CONDUCTED WITH 22 INTERVENTIONAL CARDIOLOGISTS OVERWHELMINGLY SUPPORT THE IDEA THAT SUCH PRESERVATION OF MYOCARDIAL TISSUE AND FUNCTION WOULD REPRESENT A SIGNIFICANT LONG-TERM BENEFIT TO THE PATIENTS EXPERIENCING ISCHEMIA-REPERFUSION INJURY LEADING TO A DECREASE IN THE INCIDENCE OF HEART FAILURE. PREVIOUS DATA FROM OUR LAB WITH ANOTHER COMPOUND YT-001 (IDENTICAL MECHANISM OF ACTION AS YT-002) DEMONSTRATED A SIGNIFICANT INHIBITION OF HYDROGEN PEROXIDE GENERATION IN VIVO, AND A REMARKABLE SPARING OF TISSUE DAMAGE AND CARDIAC FUNCTION POST REPERFUSION IN BOTH THE EX VIVO RAT I/R HEART AND THE IN VIVO PORCINE MYOCARDIAL I/R MODEL. HOWEVER, YT-001 HAS LIMITED SOLUBILITY AND REMAINING PATENT LIFE. OUR NEW MOLECULES (YT-002 AND YT-004) HAVE DRAMATICALLY IMPROVED SOLUBILITY, POTENCY AND NEW PATENT LIFE. WE HAVE ALREADY DEMONSTRATED IMPRESSIVE INFARCT SIZE REDUCTION AND CARDIAC FUNCTION PROTECTION IN ISOLATED RAT I/R HEARTS WITH YT-002 AND YT-004. IN THIS PROPOSAL, WE WILL EVALUATE THE CARDIO PROTECTIVE EFFECTS OF YT-002 AND YT-004 ON ISCHEMIA REPERFUSION IN THE GORMAN PIG MODEL (19). IN ADDITION TO THE ANIMAL'S VITAL SIGNS, EJECTION FRACTION (MEASURED BY ECHOCARDIOGRAPHY) WILL BE MONITORED (AS AN INDEX OF CARDIAC FUNCTION/CONTRACTILITY) AS WELL AS CARDIAC PROTEINS (E.G., TROPONIN I) AS AN INDEX OF TISSUE DAMAGE THROUGHOUT THE PROTOCOL. THREE HOURS AFTER REPERFUSION, THE HEARTS WILL BE EXCISED, AND STAINED FOR DIRECT ASSESSMENT OF CARDIAC DAMAGE (INFARCT SIZE). IMMUNOHISTOCHEMISTRY ON FROZEN HEART SECTIONS WILL BE PERFORMED IN DR. YOUNG'S LAB AT PCOM TO DETECT PKCE AND PKCSSII LOCALIZATION. BASED UPON PREVIOUSLY GENERATED PIG HEART DATA WITH THE PKCE INHIBITOR YT-001, WE EXPECT TO SEE A DRAMATIC IN VIVO PRESERVATION OF CARDIAC TISSUE AND FUNCTION COMPARED TO ANIMALS RECEIVING SCRAMBLED PEPTIDE CONTROL. THESE POSITIVE DATA WILL PROVIDE ADDITIONAL JUSTIFICATION FOR PERFORMING LONGER-TERM ANIMAL EFFICACY STUDIES AND EVENTUALLY INVESTIGATIONAL NEW DRUG (IND) ENABLING STUDIES IN SUPPORT OF HUMAN CLINICAL TRIALS.