TRAUMA PRIMES CELLS

目前的应用程序被认为是我们资助的1998年创伤中心应用程序的扩展。我们的总体假设是，我们可以设计出治疗创伤原始细胞的方法。在过去的两年中，我们的创伤/多器官功能衰竭登记研究（成人-项目IA和儿童-项目1C）招募了大量患者，我们推测应激反应基因启动子区的多态性影响对损伤后多器官功能衰竭的易感性（项目1B）。传统上认为活化的中性粒细胞与损伤后的全身性炎症有关，我们假设由于延迟的中性粒细胞凋亡导致这种损伤的加重（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）。我们扩大我们以前的询问信号机制的高渗治疗（项目IV）的机制检查。HSP 72的脂质体递送抑制Mphi TNF产生。我们进一步提出HSP 72抑制TNF受体介导的Mphi炎症反应的放大，并且HSP 72的靶向递送控制损伤后心肌炎症（项目V）。肺功能不全是在损伤后器官衰竭的连续级联中的早期受害者所认识到的。我们提出肺血管功能障碍是这个临床上令人恐惧的问题的起源（项目VI）。TNF（尽管免疫学上是健康的）现在被认为具有损伤后抑郁的潜力。我们提出了白细胞介素-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VII）。两年前，我们提出激酶/磷酸酶信号作为损伤后细胞信息传递的骨干。我们现在假设，肌膜信号内吞到细胞骨架支架调节损伤后信息传递的顺序和幅度（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MOF的独立预测因子。我们现在假设携带氧的血红蛋白是好的，但是红细胞膜脂质是坏的。我们建议破译哪些膜脂质部分会引起麻烦（项目IX），并进一步进行临床抗细胞因子试验（项目VI和VII）（不需要资金）和基于血红蛋白的氧载体复苏试验（不需要资金），我们希望这将绕过我们在早期创伤登记处（项目IA）中发现的问题（输血）。

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).