Contribution of Microglia to Axonal Injury following Repetitive Concussion in Mou

小胶质细胞对反复脑震荡后轴突损伤的贡献

基本信息

批准号：
8426662
负责人：
Rachel Elise Bennett
金额：
$ 2.54万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8426662
关键词：
Action Potentials Acute Address Alzheimer&apos s disease risk Animals Appearance Area Autopsy Axon Brain Brain Concussion Brain Injuries Cell Surface Receptors Cells Chronic Chronic Phase Corpus Callosum Data Dementia Electron Microscopy Electrophysiology (science)FCGR3B gene Flow Cytometry Head Hour Human Immune Immunohistochemistry Impaired cognition Impairment Incidence Individual Inflammatory Response Injury Interleukin-1 Interleukin-6 Invaded Ipsilateral Knowledge Lead Lesion Little&apos s Disease Macrophage-1 Antigen Magnetic Resonance Imaging Measurement Measures Methods Microglia Modeling Mus Neurites Neurons Operative Surgical Procedures Pathologic Processes Pathology Pattern Phase Phenotype Poison Population Positron-Emission Tomography Production Role Sampling Silver Staining Slice Sports Surface Techniques Therapeutic Time Tissues Toxin Training Trauma Traumatic Brain Injury Up-Regulation Work axonal degeneration brain cell cranium cytokine extracellular injured mouse model nervous system disorder neurosurgery research study response white matter

项目摘要

DESCRIPTION (provided by applicant): There are an estimated 1.6-3.8 million sports-related concussions each year. Human concussions do not usually cause macroscopic lesions visible by CT or MRI, but multiple concussions can lead to axonal injury, long-term cognitive impairments, and neurological disease. These long- term changes are best described in professional athletes, termed "dementia pugilistica" in boxers and chronic traumatic encephalopathy in other athletes. Studies in these individuals have shown that activation of the brain's resident immune cells, microglia, occurs after traumatic brain injury in areas of axonal injury. Microglial activation in white matter has also been noted after concussion in post- mortem-samples. Whether this response contributes to ongoing axonal injury, protects against further damage, or is neutral in concussion is not known. To fill this knowledge gap, our lab has developed a reproducible model of repetitive concussive injury in mouse similar to Longhi and colleagues (Neurosurgery 2005). In this model, two closed-skull impacts delivered 24 hours apart result in a consistent pattern of axon degeneration and microglial activation without neuronal cell loss. The central hypothesis of this proposal is that persistent microglial activatio following repetitive concussive injury in mouse results in axon degeneration and electrophysiological compromise. To address this hypothesis, the phenotype of microglia within white matter will be compared across time points. A microglial-specific toxin will be administered to determine how elimination of microglia effects axonal degeneration in both the acute and chronic injury phase. If successful, these experiments will greatly increase our knowledge of the role of activated microglia in axonal injury in this mouse model of repetitive concussive trauma. These results may deepen our understanding of the pathological processes that cause cognitive impairments in concussed individuals and could have important implications for therapeutics. For these experiments the applicant will be trained in multiple techniques including small animal surgery, immunohistochemistry, stereology, flow cytometry, qPCR, extracellular brain slice electrophysiology, and statistical analysis of quantitative data.

描述（由申请人提供）：估计每年有 1.6-380 万起与运动相关的脑震荡。人类脑震荡通常不会引起 CT 或 MRI 可见的宏观损伤，但多次脑震荡可导致轴突损伤、长期认知障碍和神经系统疾病。这些长期变化在职业运动员中得到了最好的描述，在拳击手中被称为“拳击手痴呆”，在其他运动员中被称为慢性创伤性脑病。对这些个体的研究表明，大脑常驻免疫细胞（小胶质细胞）的激活发生在轴突损伤区域的创伤性脑损伤后。在死后样本中，脑震荡后白质中的小胶质细胞也被激活。这种反应是否会导致持续的轴突损伤、防止进一步的损伤，或者在脑震荡中呈中性，目前尚不清楚。为了填补这一知识空白，我们的实验室开发了一种可重复的小鼠重复性脑震荡损伤模型，类似于 Longhi 及其同事 (Neurosurgery 2005)。在该模型中，相隔 24 小时进行的两次闭合颅骨撞击导致轴突变性和小胶质细胞激活的一致模式，而没有神经元细胞损失。该提议的中心假设是，小鼠重复性脑震荡损伤后持续的小胶质细胞激活会导致轴突变性和电生理学损害。为了解决这一假设，将在不同时间点比较白质内小胶质细胞的表型。将施用小胶质细胞特异性毒素，以确定小胶质细胞的消除如何影响急性和慢性损伤阶段的轴突变性。如果成功，这些实验将大大增加我们对重复性脑震荡小鼠模型中激活的小胶质细胞在轴突损伤中作用的认识。这些结果可能会加深我们对导致脑震荡个体认知障碍的病理过程的理解，并可能对治疗产生重要影响。对于这些实验，申请人将接受多种技术的培训，包括小动物手术、免疫组织化学、体视学、流式细胞术、qPCR、细胞外脑切片电生理学和定量数据的统计分析。