PARS INHIBITOR FOR CARDIAC ALLOTRANSPLANTATION

Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been implicated in the pathogenesis of allograft rejection. Triggered by peroxynitrite-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly up-regulates expression of the transcription expression of the transcription factor AP-1 and AP-1 dependent genes, including ICAM-1. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity has potent anti-inflammatory effects and prolongs cardiac allograft survival. The specific aim of the present proposal has to determine the benefit of PJ-34, a novel, non-toxic, and highly potent PARS inhibitor, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of cardiac transplant rejection. Demonstration that PJ-34 prevents tissue injury and prolongs graft survival would represent a breakthrough in the design of novel anti- inflammatory regimens to prolong allograft survival.