Immunological Complications of Radiation Combined Injury

描述(申请人提供)：核事故或袭击造成的辐射伤害和创伤，导致复合伤害。虽然复合损伤的程度因受害者的位置不同而有所不同，但历史表明，与单一形式的损伤相比，经历复合损伤的人更容易受到伤害，并发展出更严重的损伤后并发症。导致复合伤患者预后不良的机制尚不清楚。研究复合损伤对免疫系统影响的动物模型的发展将极大地促进关于复合损伤免疫并发症的研究。因此，这个阶段性创新项目的第一阶段将是通过探索不同剂量的辐射暴露和烧伤对免疫系统细胞和介质的影响来开发一种复合损伤的小鼠模型。我们将收集辐射、烧伤和辐射复合烧伤诱导的小鼠免疫生理学变化的数据。实验还将通过测试复合损伤小鼠抵抗细菌感染和败血症的能力来确定它们的免疫能力。第二阶段，本项目将利用该复合伤小鼠模型，测试使用造血生长因子或Toll样受体佐剂诱导损伤小鼠免疫细胞恢复和增强宿主对病原体的防御能力的效果。在这一阶段，我们还将测试使用抗炎治疗是否可以保护受伤的小鼠免受辐射、烧伤或联合损伤对免疫系统的有害影响。这些研究的结果将为我们和其他研究人员提供一个有效的辐射复合损伤小鼠模型，并将极大地促进我们对复合损伤如何扰乱免疫系统功能的理解。此外，测试免疫增强或抗炎治疗有效性的实验结果将提供关于哪种治疗干预可能对复合损伤受害者最有益的见解。

DESCRIPTION (provided by applicant): Nuclear accidents or attacks inflict both radiation injury and trauma resulting in a combined injury. While, the extent of the combined injury varies depending on the location of the victim, history indicates that individuals that experience combined injury succumb more readily to their injuries and develop more severe post-injury complications than patients with a single form of injury. The mechanisms responsible for the poor prognosis of combined injury victims are not know. The development of an animal model to study the effects of combined injury on the immune system would significantly advance research addressing the immune complications of combined injury. Therefore, the first phase of this phased innovation project will be to develop a mouse model for combined injury by exploring the effects of differing doses of radiation exposure and burn injury on cells and mediators of the immune system. We will collect data on immunophysiological changes in mice that are induced by radiation, by burn injury, and by combined radiation with burn injury. Experiments will also determine the immune competence of combined injured mice by testing their ability to resist bacterial infections and sepsis. The second phase this project will use this mouse model for combined injury to test the efficacy of using hematopoietic growth factor or Toll-like receptor adjuvants to induce immune cell recovery and stronger host defenses against pathogens in injured mice. During this phase, we will also test whether using counter-inflammatory treatments might protect injured mice from the detrimental effects of radiation, burn, or combined injury on the immune system. The results of these studies will provide us and other investigators with a validated mouse model for radiation combined injury and will significantly advance our understanding of how combined injury disrupts immune system function. Moreover, the findings of experiments testing the efficacy of immune-enhancing or counter-inflammatory treatments will provide insight into which therapeutic intervention might be the most beneficial to combined injury victims.