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

项目总结/摘要 创伤性损伤是美国年轻人死亡的主要原因。于民用和军事 创伤、出血和创伤性脑损伤（TBI）占这些死亡的大多数。 目前的治疗集中在出血控制，血液制品复苏和支持， 生理参数目前还没有专门预防细胞功能障碍的治疗方法， 受到惊吓或外伤我们已经证明，在创伤的临床现实模型中， 出血性休克和TBI，用非选择性组蛋白脱乙酰酶（HDAC）抑制剂治疗 提高生存率和认知功能。然而，这种效应所需的剂量一直是 非常高，引起了对毒性的关注。已知HDAC有18种亚型，我们相信 能够开发一种更有针对性的治疗方法来抑制HDAC的特定亚型， 达到所需的治疗效果，同时减少对毒性和不良反应的关注， 反应.该提案是NIH资助R 01 GM 84127工作的延续。的一部分 在这项授权中，我们在细胞系和啮齿动物中测试了各种亚型特异性HDAC抑制剂， 出血、创伤和败血性休克模型。从细胞培养数据和小动物 模型将用于选择适当的亚型特异性HDAC抑制剂，以在 出血性休克、多发性创伤（包括TBI）和脑内创伤的临床现实猪模型。 腹腔脓毒症使用这个模型，我们将能够比较长期生存和认知能力， 常规复苏、非选择性HDAC抑制剂和 同种型特异性HDAC抑制。此外，猪组织将用于阐明 导致创伤期间细胞死亡和功能障碍的潜在机制，以及如何 HDAC抑制在基因组和蛋白质组水平促进“促存活”表型。

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.