Impaired glucose utilization and behavior in a mouse model of chronic, mild TBI

慢性轻度 TBI 小鼠模型中葡萄糖利用和行为受损

• 批准号: 9405337
• 负责人: June Zhou
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405337
• 关键词: Acute; Address; Afghanistan; Anhedonia; Animals; Area; Basic Science; Behavior; Biological Markers; Brain; Brain Injuries; Brain region; Cell physiology; Cerebrum; Chronic; Chronic Phase; Clinical Research; Clinical Trials; Conflict (Psychology); Corpus Callosum; Data; Dietary Intervention; Dose; Enzymes; Exhibits; FDA approved; Functional disorder; Funding; Future; GLP-I receptor; Gene Expression; Glucose; Goals; Hippocampus (Brain); Hour; Human; Hypothalamic structure; Impairment; Inflammation; Injury; Intervention; Investigation; Iraq; Knockout Mice; Lead; Lobe; Longitudinal Studies; Maze Learning; Measures; Memory; Memory Loss; Methods; Modeling; Molecular; Motor; Mus; Neurons; Neurosecretory Systems; Occipital lobe; Outcome; Parietal Lobe; Pathogenesis; Patients; Phase; Physical activity; Proteins; Recovery; Recovery of Function; Rehabilitation therapy; Research; Rodent; Rodent Model; Sleep; Sucrose; TBI treatment; Temporal Lobe; Testing; Thalamic structure; Time; Traumatic Brain Injury; Veterans; Water; Work; analog; base; behavioral impairment; combat; cranium; disability; experimental study; glucagon-like peptide 1; glucose metabolism; improved; incretin hormone; mild traumatic brain injury; morris water maze; mouse model; neurobehavioral; nutrition; pre-clinical; preclinical study; preference; protein expression; public health relevance; response; targeted therapy trials; therapeutic development; translational study

DESCRIPTION (provided by applicant): Mild-moderate traumatic brain injury (mTBI) is the "signature injury" of both Iraq and Afghanistan conflicts and leads to significant disability. During the chronic phase of mTBI, a consistent funding is a decreased cerebral glucose utilization in both humans and animals. Glucose and its intermediate metabolites are essential fuels to maintain neuronal cell function. The decreased supply of glucose and its intermediary metabolite in the brain also lead to memory loss, a common findings in patients with mTBI. To date, strategies that target improvements in brain glucose utilization have not been employed in paradigms for mTBI rehabilitation. Objective: using mouse model of mTBI to study long-term effects of mTBI on brain glucose utilization, neurobehavioral recovery, and their inter-relationships. Specific aims: (1) to longitudinally characterize and modify an established mouse mTBI model that demonstrates persistent neurobehavioral impairments, (2) to determine whether such impairments are associated with altered expression of proteins and genes related to glucose utilization in discrete brain areas, and (3) to assess as a "proof of concept" whether augmenting endogenous incretin hormone, GLP-1, via a specific dietary intervention ameliorates these chronic neurobehavioral and biomarker abnormalities. Hypothesis: (1) Chronic mTBI decreases expression of glucose utilization related transporters and enzymes in specific brain regions, in association with impaired neurobehavioral functions. (2) Augmentation of endogenous GLP- 1during the post-acute phase of TBI improves expression of brain glucose utilization related transporters/enzymes and related neurobehavioral outcomes in the above mTBI model. Methods: The repetitive mild closed-skull traumatic brain injuries within 24 or 96 hours will be used to generate mouse model of mTBI. This mouse mTBI model will be used for three experiments proposed: (1) determining the time course of chronic (> 7 weeks) neurobehavioral impairments in this mouse mTBI model: Morris water maze for learning and memory test; the rotarotor for motor coordination; and 2-bottle sucrose/water preference test for anhedonia; (2) measuring the temporal relationships between neurobehavioral impairments and expression of glucose utilization related transporters and enzymes in discrete brain regions, such as cortex (frotal lobe, parietal lobe, temporal lobe and occipital lobe), corpus callosum, hippocampus, thalamus, and hypothalamus; (3) examining whether increasing endogenous GLP-1 by a specific dietary intervention enhances expression of glucose utilization related biomarkers and neurobehavioral recovery in mTBI mice. The results from proposed studies will provide necessary data for further collaborative researches that will inform additional basic science and translational investigations on chronic phase of mTBI; and for more detailed cellular and molecular mechanistic studies on prolonged decreased brain glucose utilization following mTBI. Our long term goal is to improve the management of mTBI in both Veterans and non-Veterans, based upon reversing their impaired brain glucose metabolism.

描述（由申请人提供）： 轻度中度的脑损伤（MTBI）是伊拉克和阿富汗冲突的“签名损伤”，导致严重的残疾。在MTBI的慢性阶段，一致的资金是人类和动物的脑葡萄糖利用率降低。葡萄糖及其中间代谢产物是维持神经元细胞功能的必需燃料。葡萄糖及其中介代谢物在大脑中的供应减少也导致记忆力丧失，这是MTBI患者的常见发现。迄今为止，尚未在MTBI康复的范式中采用针对大脑葡萄糖利用率改善的策略。目的：使用MTBI的小鼠模型研究MTBI对脑葡萄糖利用率，神经行为恢复及其相互关系的长期影响。具体目的：（1）纵向表征和修改已建立的小鼠MTBI模型，该模型证明了持续的神经行为障碍，（2）确定这种损害是否与蛋白质和基因的表达和基因的表达改变相关，并通过离散的大脑区域中的葡萄糖利用与（3）相关的（3）的特定概念，以评估“特定于概念”，以上是“对概念”的培训，是否旨在“促进”是否构成了“促进”，是否是“对概念的培养”，是否是“促进的”。干预可以改善这些慢性神经行为和生物标志物异常。假设：（1）慢性MTBI降低了特定脑区域中葡萄糖利用相关转运蛋白和酶的表达，以及神经行为功能受损。 （2）增强内源性GLP-1D的TBI急性后阶段改善了上述MTBI模型中脑葡萄糖利用相关转运蛋白/酶的表达和相关的神经行为结果。方法：将在24或96小时内重复的轻度闭合胸腔外伤性脑损伤用于生成MTBI的小鼠模型。该小鼠MTBI模型将用于三个实验：（1）在该小鼠MTBI模型中确定慢性（> 7周）神经行为障碍的时间过程：莫里斯水迷宫用于学习和记忆测试；电动机协调的旋转旋转器；和2瓶蔗糖/水的偏好测试； （2）测量神经行为损伤与葡萄糖利用率相关转运蛋白和酶的表达之间的时间关系，例如皮层（Frotal Lobe，Parietal Lobe，Paretal Lobe，Paretal Lobe，Paretal Lobe和cocipital Lobe），Corpusum callosum，callosum callosum，callosum，Hippocampus，Hippocampus，thalamus和Hypothalamus和Hypothalamus和Hypothalamus; （3）检查通过特定的饮食干预增加内源性GLP-1是否会增强MTBI小鼠中葡萄糖利用相关的生物标志物和神经行为恢复的表达。拟议研究的结果将为进一步的协作研究提供必要的数据，这些数据将为MTBI慢性阶段的其他基础科学和翻译调查提供信息；对于更详细的细胞和分子机械研究，MTBI后长期降低了脑葡萄糖利用率。我们的长期目标是基于逆转其脑葡萄糖代谢受损而改善退伍军人和非退伍军人的MTBI管理。