Isoform Specific Histone Deacetylase Inhibitor Treatment in a Swine Model of Polytrauma and Sepsis

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PROJECT SUMMARY/ABSTRACT Traumatic injuries are the leading cause of death in young Americans. In civilian and military trauma, hemorrhage and traumatic brain injuries (TBI) account for the majority of these deaths. Current treatment is focused on hemorrhage control, blood product resuscitation and support of physiologic parameters. No therapy exists to specifically prevent cellular dysfunction that occurs with shock or traumatic injuries. We have shown that in clinically realistic models of trauma, hemorrhagic shock and TBI, treatment with nonselective histone deacetylase (HDAC) inhibitors improves survival and cognitive function. However, the doses needed for this effect have been very high, raising concern for toxicity. There are 18 known isoforms of HDAC, and we believe that being able to develop a more targeted therapy to inhibit specific isoforms of HDAC would achieve the desired therapeutic effect while decreasing concern for toxicity and adverse reactions. This proposal is a continuation of work done on NIH grant R01GM84127. As part of this grant, we have tested various isoform specific HDAC inhibitors in cell line and rodent models of hemorrhage, trauma and septic shock. Work from cell culture data and small animal models will be used to select the appropriate isoform specific HDAC inhibitors to test in a clinically realistic swine model of hemorrhagic shock, polytrauma including TBI and intra- abdominal sepsis. Using this model, we will be able to compare long term survival and cognitive outcomes after treatment with conventional resuscitation, nonselective HDAC inhibitor and isoform specific HDAC inhibition. Additionally, tissue from swine will be used to elucidate underlying mechanisms that contribute to cell death and dysfunction during trauma, and how HDAC inhibition promotes a “pro-survival” phenotype at the genomic and proteomic level.