TRAUMA PRIMES CELLS

创伤引发细胞

• 批准号: 6919553
• 负责人: ANIRBAN BANERJEE
• 金额: $ 43.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919553
• 关键词: ischemia; multiple organ failure; reperfusion; trauma

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).

当前的应用被认为是我们1998年创伤中心申请的扩展。我们的全球假设是我们可以为创伤素细胞设计治疗。在过去的两年中，我们喜欢将患者招募到我们的创伤/MOF登记处（成人项目IA和儿童项目1C）中，并假设在压力反应基因的启动子区域中的多态性会影响对伤害后MOF的敏感性（项目1B）。传统上，激活的嗜中性粒细胞与伤害后的全身性炎症有关，我们假设由于中性粒细胞凋亡的延迟而导致这种损伤加剧（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特征，作为表明创伤后事件的信号（项目III）。我们将先前对信号传导机制的询问扩展到检查高渗治疗机制（项目IV）。 HSP72的脂质体递送抑制MPHI TNF的产生。我们进一步提出，HSP72抑制了TNF受体介导的MPHI炎症反应的扩增，并靶向HSP72控制在伤害后心肌炎症后控制（Project V）。肺部功能障碍是在造成伤害后器官失败的顺序级联中的早期受害者所承认的。我们建议肺部血管舒缩功能障碍是这个临床上令人恐惧的问题的起源（项目VI）。 TNF（尽管免疫学上健康）现在因其伤害后的抑郁潜力而被认可。我们提出了针对白介素18的机制和治疗，作为一种更近端的“失控”细胞因子（VII项目）。两年前，我们提出激酶/磷酸酶信号传导是伤害后细胞信息传播的骨干。现在，我们假设肌膜信号内吞作用在细胞骨架脚手架上调节伤害后信息转移的序列和幅度（项目VIII）。令我们惊讶的是，流血（我们很高兴地翻译为震惊的替代物）被证明是后MOF的独立预测指标。现在，我们假设携带血红蛋白的氧气很好。但是，红细胞膜脂质块不好。我们建议解释哪些膜脂质部位会引起麻烦（IX项目），然后我们将进行临床抗周围因子试验（项目VI和VII项目）（无需要求提供资金），并通过基于血红蛋白的氧气载体（无需资金要求）进行复苏试验，我们希望该问题迅速汇总（血液经营），我们将识别出（我们的经验）。