Combined radiation and traumatic injury affect hippocampal structure and function

描述(申请人提供)：在放射性/核恐怖主义的情况下，辐射暴露很可能与另一种侮辱相结合，如创伤。虽然辐射复合损伤(RCI)被认为是一个具有重要意义的领域，但关于辐射与其他形式的损伤之间相互作用的机制，或者什么对策可能有效地改善这种变化，通常很少有数据。不受控制的辐射暴露必然涉及广泛的辐射剂量和随后的组织/身体影响，直至并包括所描述的致命辐射综合征。但是，在低于致死阈值的剂量下，或者如果干预措施能够调节关键早期反应组织(例如骨髓、肠道)的辐射反应，其他组织(例如脑)的反应可能会变得更成问题。这一可能的情况在随后或伴随的损伤(即RCI)的情况下可能特别相关，这可能会加剧潜在的或“轻微的”辐射损伤，并导致最终可能影响器官功能的细胞/组织损伤。创伤性脑损伤可能是核爆炸的后果，当个人暴露在爆炸性力量中时，它是一种常见的死亡和残疾原因。关于大脑，众所周知，辐射和创伤都会导致特定的海马区依赖损伤，涉及空间学习和记忆。这种认知障碍的发病机制可能是多方面的，我们假设RCI将对神经发生、由即刻早期基因Arc(活性调节细胞骨架相关蛋白)的分子分布评估的神经元功能和行为表现产生不利影响。我们进一步认为，这些效应部分是由神经炎症介导的，使用多胺抑制剂α-二氟甲基鸟氨酸(DFMO)减少激活的小胶质细胞数量将缓解RCI的这些不利影响。使用成熟的动物模型，以及在mRNA和蛋白质表达水平上测量神经元活动史(即Arc)的创新方法，我们将分析与神经发生和神经炎症相关的特定细胞和分子因素，并确定当两种侮辱同时给予或分开30天时，它们是否与RCI后海马区依赖行为的测量相关。了解RCI的发病机制对于制定缓解或治疗策略是至关重要的，并可能对提高损伤后的生活质量产生重大影响。在放射性/核恐怖主义的背景下，辐射暴露很可能与另一种侮辱，如创伤，即辐射复合损伤(RCI)一起发生。对于大脑，涉及创伤性损伤的RCI可能会导致细胞损伤，最终可能影响组织功能和行为表现。了解RCI对大脑的细胞、分子和功能后果对于制定缓解或治疗策略至关重要，并可能对改善损伤后的生活质量产生重大影响。

DESCRIPTION (provided by applicant): In the context of radiological/nuclear terrorism, radiation exposure will likely occur in combination with another insult, such as trauma. While radiation combined injury (RCI) is recognized as an area of great significance, there generally are few data regarding the mechanisms underlying the interactions between irradiation and other forms of injury, or what countermeasures might be effective in ameliorating such changes. Uncontrolled radiation exposure will necessarily involve a wide range of delivered doses and subsequent tissue/body effects, up to and including the well-described and lethal radiation syndromes. But at doses below the threshold for lethality, or if interventions are able to modulate the radiation response of critical early responding tissues (e.g. bone marrow, gut), the response of other tissues (e.g. brain), may become more problematic. This possible scenario may be particularly relevant in the context of a subsequent or concomitant injury (i.e. RCI), which could exacerbate latent or 'mild' radiation injury, and result in cellular/tissue injury that could ultimately impact organ function. Traumatic brain injury is a likely consequence of a nuclear blast, and is a frequent cause of death and disability when individuals are exposed to explosive forces. With respect to the brain, irradiation and traumatic injury are both known to induce specific hippocampal-dependent impairments that involve spatial learning and memory. The pathogenesis of such cognitive impairment is likely multifaceted, and we hypothesize that RCI will adversely affect neurogenesis, neuronal function as assessed by the molecular distribution of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein), and behavioral performance. We further contend that these effects are mediated, in part, by neuroinflammation, and that reducing the numbers of activated microglia using the polyamine inhibitor a-difluoromethylornithine (DFMO), will ameliorate these adverse effects of RCI. Using well-established animal models, along with an innovative approach of measuring neuronal activity history (i.e. Arc) at the level of mRNA and protein expression, we will analyze specific cellular and molecular factors associated with neurogenesis and neuroinflammation, and determine if they correlate with measures of hippocampal dependent behavior after RCI when the 2 insults are given concomitantly or when they are separated by 30 days. Understanding the pathogenesis of RCI is essential for the development of mitigation or treatment strategies and may have a significant impact in improving post-injury quality of life. In the context of radiological/nuclear terrorism, radiation exposure will likely occur in combination with another insult, such as trauma, i.e. radiation combined injury (RCI). With respect to the brain, RCI involving traumatic injury may result in cellular injury that could ultimately impact tissue function and behavioral performance. Understanding the cellular, molecular and functional consequences of RCI to the brain is crucial for the development of mitigation or treatment strategies and may have a significant impact in improving post-injury quality of life.