Mitigation of Brain Inflammation and Cognitive Impairment after Radiation Injury

减轻放射损伤后的脑部炎症和认知障碍

• 批准号: 8010008
• 负责人: M. KERRY O'BANION
• 金额: $ 39.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010008
• 关键词: Accidents; Acute; Address; Adult; Adverse effects; Affect; Animal Model; Animals; Antibiotics; Behavioral; Blood - brain barrier anatomy; Bone Marrow Transplantation; Brain; Brain Edema; Brain Neoplasms; Burn injury; Cells; Child; Childhood; Chronic; Cognitive; Cognitive deficits; Confusion; Development; Disasters; Dose; Dose-Limiting; Drowsiness; Encephalitis; Endothelial Cells; Event; External Beam Radiation Therapy; Functional disorder; Glucocorticoids; Goals; Hippocampus (Brain); Immune; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Injury; Intercellular Junctions; Intervention; Learning; Life; Link; Lipopolysaccharides; Measures; Memory; Microglia; Minocycline; Modeling; Mus; Myeloid Cell Activation; Nervous System Trauma; Neural Inhibition; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neurologic; Nitrogen; Nuclear; Outcome; Oxidative Stress; Oxygen; Peripheral; Pharmaceutical Preparations; Pilot Projects; Population; Procedures; Process; Production; Radiation; Radiation Injuries; Radiation therapy; Radiation-Induced Change; Reactive Oxygen Species; Reporting; Repression; Structure; Synapses; Syndrome; Systemic infection; T-Lymphocyte; Testing; Time; Whole-Body Irradiation; Work; base; brain irradiation injury; cancer therapy; catalase; chemokine; cognitive change; cognitive function; cytokine; in vivo; indexing; internal radiation; macrophage; mimetics; mouse model; nerve stem cell; neurogenesis; neuroinflammation; postnatal; radiation effect; synaptic function

Neurocognitive deficits are cleariy associated with radiation therapy, particulariy in children where they represent a major detrimental side effect of life-saving procedures. Long-standing changes in brain function have also been described in individuals exposed to radiafion in the setting of radiological accidents (e.g Chernobyl). Although not as dramatic or life threatening as the classic syndromes associated with lethal and sub-lethal radiafion exposure, radiafion-induced changes in cognitive capacity will likely present a significant and life-long burden to individuals surviving a radiological accident or nuclear disaster. Accumulating evidence suggests that brain radiafion injury leads to a persistent alterafion in the brain's milieu, manifest in animal models over many months as acfivafion of endogenous glial cells, recruitment of peripheral immune cells, and chronic elevation of cytokines, chemokines, and reactive oxygen and nitrogen species. We hypothesize that this neuroinflammatory milieu contributes to neurocognifive deficits, including inhibifion of hippocampal neurogenesis and synapfic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinfiammafion and/or producfion of ROS can mifigate radiation-induced changes in infiammatory cell populafions, expression of cytokines, producfion of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure condifions (external and internal radiafion) and in newly born animals where we expect the effects to be enhanced. We will also determine whether radiafion exposed animals are primed for greater neurocognitive deficits following challenge with lipopolysaccharide, a "second hit" known to alter learning and memory. Finally, we will explore the possibility that total body irradiation combined with thermal burn exacerbates central nervous system effects. Specific outcomes of this project will include development of 4 mouse models for investigafing the relafionship between brain radiation injury and cognitive deficits, as well as tesfing of three drugs, each acfing through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.

神经认知缺陷与放射治疗明显相关，特别是在儿童中， 这是救生程序的主要副作用。大脑功能的长期变化 在辐射事故中暴露于辐射的个体中也有描述（例如 切尔诺贝利）。虽然不像典型的致命和致命的综合征那样戏剧性或危及生命， 亚致死辐射暴露，辐射诱导的认知能力变化可能会呈现出显着的 对在放射性事故或核灾难中幸存的个人来说是终身的负担。积累 有证据表明，脑辐射损伤导致脑环境的持续改变，表现在 在许多个月的动物模型中，内源性神经胶质细胞的激活，外周免疫细胞的募集， 细胞，以及细胞因子、趋化因子和活性氧和氮物质的慢性升高。我们 假设这种神经炎性环境导致神经认知缺陷，包括 海马神经发生和突触功能。因此，拟议研究的主要目标是 确定使用抑制神经炎症和/或ROS产生的药物是否可以增加 放射诱导的炎症细胞群的变化、细胞因子的表达、ROS的产生， 海马神经发生和神经认知作用。我们将在成年小鼠中探索这一假设， 两种暴露条件（外部和内部辐射）和新生动物，我们预计 效果有待加强。我们还将确定辐射暴露的动物是否准备好更大的 脂多糖挑战后的神经认知缺陷，一种已知会改变学习和 记忆最后，我们将探讨全身照射结合热烧伤的可能性， 加重中枢神经系统的影响。该项目的具体成果将包括开发4个 小鼠模型，用于研究脑辐射损伤和认知缺陷之间的关系，以及 作为对三种药物的测试，每种药物通过不同的机制来减轻神经炎症状态。 并可能恢复认知能力。