TRAUMA PRIMES CELLS

目前的申请被认为是我们1998年资助的创伤中心申请的延伸。我们的全球假设是，我们可以设计出治疗创伤原始细胞的方法。在过去的两年里，我们在我们的创伤/多器官功能衰竭登记系统(成人-项目IA和儿童-项目1C)中招募了令人满意的患者，我们假设应激反应基因启动子区的多态影响损伤后多器官功能衰竭的易感性(项目1B)。传统上，激活的中性粒细胞与损伤后的全身炎症有关，我们假设这种损伤的恶化是由于延迟的中性粒细胞凋亡(项目II)。细胞/器官/患者缺血是任何重大损伤的标志，我们希望探索这种改变的细胞生物能谱作为指示创伤后事件的信号(项目III)。我们将我们之前对信号机制的询问扩展到对高渗治疗机制的研究(项目IV)。脂质体注射HSP72可抑制Mphi肿瘤坏死因子的产生。我们进一步提出，HSP72抑制肿瘤坏死因子受体介导的MPHI炎症反应的放大，靶向递送HSP72控制损伤后的心肌炎症(项目V)。肺功能障碍是在损伤后器官衰竭的连续级联反应中被早期患者认识到的。我们建议肺血管运动功能障碍是这一临床可怕问题的根源(方案VI)。肿瘤坏死因子(尽管在免疫上是健康的)现在被认为是损伤后的抑郁潜在性。我们提出了白介素18作为一种更接近“失控”的细胞因子的机制和治疗方法(项目七)。两年前，我们提出将激酶/磷酸酶信号转导作为损伤后细胞信息传递的主干。我们现在假设，肌膜信号在细胞骨架上的内吞作用调节了损伤后信息传递的顺序和大小(项目VIII)。令我们惊讶的是，输血(我们很高兴地将其翻译为休克的替代品)被证明是创伤后多器官功能衰竭的独立预测因子。我们现在假设携带氧气的血红蛋白是好的；但是，红细胞膜的脂质碎片是不好的。我们建议破译哪些膜脂部分会引起麻烦(项目IX)，并将进一步进行临床抗细胞因子试验(项目VI和项目VII)(没有申请资金)和基于血红蛋白的氧气载体的复苏试验(没有申请资金)，我们希望这将绕过我们在早期创伤登记中发现的一个问题(输血)(项目IA)。

This current application is conceived as an extension of our funded 1998 Trauma Center application. Our GLOBAL HYPOTHESIS is that we can devise THERAPY FOR TRAUMA PRIMES CELLS. During the past two years, we have enjoyed gratifying recruitment of patients into our Trauma/MOF Registries (ADULTS-Project IA and Children-Project 1C) and we postulate that polymorphisms in the promoter region of stress- response genes influence the susceptibility to post-injury MOF (Project 1B). Activated neutrophils have traditionally been linked to post-injury systemic inflammation and we postulate an exacerbation of this injury due to delayed neutrophil apoptosis (Project II). Cells/organs/patient ischemia is the hallmark of any major injury and we wish to explore this altered cellular bioenergic profile as signal dictating post-traumatic events (Project III). We expand our previous interrogation of signaling mechanisms to an examination of mechanisms of hyperosmolar therapy (Project IV). Liposomal delivery of HSP72 inhibits Mphi TNF production. We further propose that HSP72 suppresses TNF receptor mediated amplification of Mphi inflammatory response and that targeted deliver of HSP72 controls post-injury myocardial inflammation (Project V). Lung dysfunction is acknowledged by an early victim in the sequential cascade of post-injury organ failure. We propose pulmonary vasomotor dysfunction to be the origin of this clinically frightening problem (Project VI). TNF (although immunologically healthy) is now recognized for its post-injury depressive potential. We propose both mechanisms of and therapy against interleukin-18 as an even more proximal "out of control" cytokine (Project VII). Two years ago, we proposed kinase/phosphatase signaling as the backbone of post-injury cellular message transmission. We now postulate that sarcolemmal signal endocytosis onto a cytoskeletal scaffolding regulates the sequence and magnitude of post-injury information transfer (Project VIII). To our surprise, blood transfusion (which we had happily translated as a surrogate for shock) proved to be an independent predictor of post- traumatic MOF. We now postulate that the oxygen carrying hemoglobin is good; but, the red cell membrane lipid bits are bad. We propose to decipher which membrane lipid parts cause trouble (Project IX) and further we will conduct clinical anti-cytokine trials (Projects VI and VII) (no funding requested) and a resuscitative trial with a hemoglobin based oxygen carrier (no funding requested) which we hope will bypass a problem (blood transfusion) that we identified in our early Trauma Registry (Project IA).