The role of microglia in acute pathology of repeated concussion and CTE development

小胶质细胞在反复脑震荡和 CTE 发展的急性病理学中的作用

基本信息

批准号：
8932608
负责人：
AMANDA BOLTON-HALL
金额：
$ 2.75万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-08-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8932608
关键词：
Acute Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Anxiety Appearance Astrocytes Astrocytosis Athletic Attenuated Behavioral Biological Assay Blood - brain barrier anatomy Brain Brain Concussion Brain Injuries Case Study Cell Death Cessation of life Chronic Clinical Closed head injuries DNA-Binding Proteins Data Development Diagnosis Enzyme-Linked Immunosorbent Assay Exhibits Functional disorder Goals Human Ibuprofen Individual Inflammation Inflammatory Response Injury Knowledge Laboratories Lead Learning Link Mediator of activation protein Memory Memory impairment Microglia Military Personnel Modeling Molecular Molecular Profiling Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Pathology Penetrating Brain Injury Pharmaceutical Preparations Phosphotransferases Progranulin Proteins Randomized Reporting Risk Rodent Model Role Sports Stab Wounds Symptoms Testing Therapeutic Intervention Time Tissues Training Traumatic Brain Injury United States Western Blotting age related anxiety-like behavior astrogliosis axon injury behavior test catalyst chronic traumatic encephalopathy combat cytokine cytotoxic early onset high risk hyperphosphorylated tau in vivo injured innovation mild traumatic brain injury motor deficit mouse model neurobehavioral neuropathology novel progressive neurodegeneration public health relevance repaired response tau aggregation tau-1 tool

项目摘要

DESCRIPTION (provided by applicant): In the United States, 70-90% of the approximately 1.7-3.8 million traumatic brain injuries (TBI) reported every year are considered "mild" and result in a wide range of acute symptoms, the cause of which are not well understood. Individuals involved in activities such as the military and athletics are at increased risk of accruing multipl TBIs. Due to natural variability involved in cases of repeated concussions in humans, animal models are instrumental in expanding our knowledge regarding the cellular consequences of mild TBI, which can include axonal injury, astrocytosis and microgliosis. Acute microglial activation may contribute to early tissue damage but has also been observed chronically after TBI and in many cases of neurodegenerative diseases where neurobehavioral consequences are evident. However, to our knowledge, no studies have focused on how microglia activation specifically affects the pathological outcomes of repeated mild TBI. We have developed a closed head injury (CHI) mouse model of concussion in which repeated concussive impacts, but not a single impact, result in acute microglial activation that is associated with greater neuron death and astrogliosis. To better understand the role of microglia in the pathology of repeated concussion, posttraumatic microgliosis will be amplified or attenuated in Aim 1. Progranulin-deficient (GRN KO) mice, which exhibit increased microgliosis compared to wildtype (WT) mice after a stab wound to the brain, will be used to elicit an enhanced microglial response after three concussions delivered at 24h inter-injury intervals. Ibuprofen, a common anti-inflammatory drug, will be given to a subset of WT mice after each injury to attenuate the normal CHI-induced microglial response. Memory, motor coordination, and anxiety-like behaviors, as well as axonal injury, neuronal degeneration, and astrocytosis will be evaluated in these three groups over the first 2 weeks after injury to test the hypothesis that neuropathological damage is proportional to early microglial activation. Persistent microgliosis is associated with a condition of progressive neurodegeneration after repeated mild TBI, termed chronic traumatic encephalopathy (CTE). CTE is officially diagnosed by cytosolic accumulations of phosphorylated TAR DNA binding protein 43 (pTDP43) and hyperphosphorylated Tau in the post-mortem brain. Currently, no animal model of TBI replicates all of these key pathological hallmarks, hindering progress in understanding the causative cellular and molecular factors underlying CTE. GRN KO mice have an age- dependent increase in microgliosis (~7mo) in the absence of injury that precedes the accumulation of pTDP43 (~12-18mo). In Aim 2, chronic histopathological and behavioral effects of repeated concussions will be compared in GRN KO and WT mice over time. We anticipate that persistent activation of microglia in brain- injured GRN KO mice will accelerate pTDP43 accumulation and worsen behavioral deficits, providing a more rapid and efficient model for assessing the links between repeated concussions and the development of CTE pathology. An animal model of CTE will also provide a platform for testing therapeutic interventions.

描述（由申请人提供）：在美国，每年报告的大约17-380万外伤性脑损伤（TBI）中，有70-90％被认为是“轻度”的，结果在广泛的急性症状中，其原因尚不清楚。参与军事和田径运动等活动的个人有增加乘以TBI的风险。由于人类反复脑震荡的病例所涉及的自然变异性，动物模型对我们对轻度TBI的细胞后果的了解有助于，其中可能包括轴突损伤，星形胶质细胞增多症和小胶质细胞增多。急性小胶质细胞激活可能会导致早期组织损伤，但在TBI后慢性观察到，在许多神经退行性疾病的情况下，神经行为后果很明显。但是，据我们所知，没有研究集中于小胶质细胞激活如何专门影响重复轻度TBI的病理结果。我们已经开发了脑震荡的闭合头部损伤（CHI）小鼠模型，其中重复脑震荡影响，但没有单一影响，导致急性小胶质细胞激活与更大的神经元死亡和星形胶质细胞增多有关。为了更好地了解小胶质细胞在反复脑震荡的病理中的作用，在AIM 1中会放大或减弱小胶质细胞增多。与大脑相比，与大脑刺伤后，相比，野生型（WT）的响应增强了，在AIM 1中，小胶质蛋白缺乏症（GRN KO）小鼠会增加小胶质细胞的小鼠，而小胶质细胞增多会增加。脑震荡以24h的伤害间隔进行。布洛芬是一种常见的抗炎药，每次受伤后，将给予一部分WT小鼠，以减轻正常的CHI诱导的小胶质细胞反应。记忆，运动协调和焦虑症行为以及轴突损伤，神经元变性和星形细胞增多症将在受伤后的前2周内在这三组中评估，以检验神经病理学损害与早期微毛体激活成正比的假设。持续的小胶质细胞增多与重复轻度TBI后的进行性神经退行性的状况有关，称为慢性创伤性脑病（CTE）。 CTE通过磷酸化的TAR DNA结合蛋白43（PTDP43）和验尸脑中的高磷酸化TAU正式诊断。目前，没有TBI的动物模型复制所有这些关键的病理标志，阻碍了CTE上的病因细胞和分子因素的进展。 GRN KO小鼠在没有损伤的情况下，在PTDP43（〜12-18MO）的积累之前，小胶质细胞增多症（〜7MO）的年龄依赖性增加。在AIM 2中，随着时间的推移，将在GRN KO和WT小鼠中比较重复脑震荡的慢性组织病理学和行为效应。我们预计，在脑损伤的GRN KO小鼠中，小胶质细胞的持续激活将加速PTDP43的积累并恶化行为缺陷，从而为评估反复脑震荡与CTE病理学发展之间的联系提供了更快，更有效的模型。 CTE的动物模型还将提供一个测试治疗干预措施的平台。