Combined radiation and traumatic injury affect hippocampal structure and function

辐射和创伤联合影响海马结构和功能

• 批准号: 8103421
• 负责人: JOHN R. FIKE
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103421
• 关键词: Adverse effects; Affect; Anabolism; Animal Model; Area; Behavior; Behavioral; Blast Cell; Bone Marrow; Brain; Cause of Death; Cells; Cognition; Cognitive; Cranial Irradiation; Cytoskeleton; DL-alpha-Difluoromethylornithine; Data; Development; Dose; Hippocampus (Brain); Immediate-Early Genes; Impaired cognition; Impairment; Individual; Inflammation; Injury; Intervention; Learning; Measures; Mediating; Memory; Messenger RNA; Microglia; Molecular; Morphology; Neurons; Nuclear; Organ; Pathogenesis; Performance; Polyamines; Proteins; Quality of life; Radiation; Radiation Injuries; Radiation Syndromes; Recording of previous events; Structure; Synaptic Transmission; Terrorism; Tissues; Trauma; Traumatic Brain Injury; behavior measurement; cell injury; dentate gyrus; disability; improved; inhibitor/antagonist; innovation; irradiation; neurogenesis; neuroinflammation; protein expression; radiation adverse effect; response; treatment strategy

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.

描述（由申请人提供）：在放射性/核恐怖主义的背景下，辐射暴露可能会与另一种侮辱（如创伤）一起发生。虽然辐射复合损伤（RCI）被认为是一个非常重要的领域，但通常很少有关于辐射与其他形式损伤之间相互作用的机制的数据，或者什么对策可能有效地改善这种变化。不受控制的辐射照射必然涉及大范围的剂量和随后的组织/身体效应，直至并包括描述良好的致命辐射综合征。但是，在剂量低于致死阈值时，或者如果干预措施能够调节关键的早期反应组织（如骨髓、肠道）的辐射反应，其他组织（如大脑）的反应可能会变得更成问题。这种可能的情况可能与后续或伴随性损伤（即RCI）特别相关，这可能加剧潜在或“轻度”辐射损伤，并导致最终可能影响器官功能的细胞/组织损伤。创伤性脑损伤很可能是核爆炸的后果，当个人暴露于爆炸力时，这是造成死亡和残疾的常见原因。就大脑而言，辐射和创伤性损伤都可诱发涉及空间学习和记忆的特异性海马依赖性损伤。这种认知障碍的发病机制可能是多方面的，我们假设RCI会对神经发生、神经元功能（通过即时早期基因Arc（活性调节的细胞骨架相关蛋白）的分子分布来评估）和行为表现产生不利影响。我们进一步认为，这些影响部分是由神经炎症介导的，使用多胺抑制剂a-二氟甲基鸟氨酸（DFMO）减少激活的小胶质细胞的数量，将改善RCI的这些不良影响。使用完善的动物模型，以及在mRNA和蛋白质表达水平上测量神经元活动历史（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，并确定它们是否与RCI后海马依赖行为的测量相关，当两种损伤同时给予或分开30天时。了解RCI的发病机制对于制定缓解或治疗策略至关重要，并可能对改善伤后生活质量产生重大影响。在放射性/核恐怖主义的背景下，辐射暴露可能会与另一种侮辱（如创伤）一起发生，即辐射复合损伤（RCI）。就大脑而言，涉及创伤性损伤的RCI可能导致细胞损伤，最终影响组织功能和行为表现。了解RCI对大脑的细胞、分子和功能影响对于制定缓解或治疗策略至关重要，并可能对改善损伤后生活质量产生重大影响。