Aging and Inflammation in Mild Traumatic Brain Injury

描述(由申请人提供)： 在最近与战争有关的冲突中，创伤性脑损伤(TBI)已成为影响很大比例退伍军人的标志性损伤。在退伍军人和平民人群中，轻度创伤性脑损伤(mTBI，又称脑震荡)约占所有脑损伤的70%-80%。虽然大多数mTBI的明显症状在受伤后几天或几周内自发消失，但在10%-20%的mTBI患者中，一些功能缺陷仍然存在，最近的估计表明，多达44%-50%的mTBI患者在受伤后一年内经历三种或三种以上的症状。重复性mTBI特别令人感兴趣，因为军事人员在其一生中经常有几次mTBI暴露，可能在一次部署中。反复出现的脑损伤，即使是轻微的，也可能会干扰神经心理的恢复。反复脑震荡也与慢性创伤性脑病(CTE)有关，CTE是一种神经退行性疾病，具有进行性记忆和认知障碍，以及抑郁、焦虑和运动异常。在已提出的神经退行性疾病的环境危险因素中，脑外伤，包括轻微的脑外伤，可能是最一致的启动分子级联反应并引发神经退行性变导致阿尔茨海默病(AD)、帕金森病(PD)和肌萎缩侧索硬化症的候选因素之一。因此，脑外伤被证明可以加速AD遗传模型中的病理和行为缺陷，或者增强对帕金森病诱导的神经毒素的易感性。最近的证据也证实了脑外伤是额颞叶痴呆(FTD)的环境危险因素，FTD是一种早发性痴呆，其行为变异与行为异常、丧失社交能力或冲动和非理性行为有关。我们的初步研究表明，使用受控冲击器对小鼠头部进行轻微重复撞击(闭合性头部损伤)会导致损伤后3个月神经胶质增生、脑白质改变和认知障碍。另外，我们发现巨噬细胞集落刺激因子(CSF1)是造血系统中的关键生长因子，在急性脑损伤后全身应用时具有显著的神经保护作用。这些作用是通过CSF1受体(CSF1R)介导的，至少部分是由受损神经元表达的。在我们的模型中，新发现的这种受体的第二个配体IL-34似乎与CSF1一样有效或更有效。最重要的是，对于这一建议，初步研究表明，在我们的mTBI模型中，单次注射CSF1可以显著恢复记忆障碍和减少胶质细胞增生。基于这些初步数据，我们假设，对中枢神经系统的轻微创伤性侮辱会导致小鼠长期的神经行为缺陷，这部分模拟了在人类mTBI患者中观察到的缺陷，即使在给予CSF1和IL-34几天或几周后，全身治疗也能减轻脑损伤和相关的行为缺陷。 受伤。在这项应用中，我们建议改进我们的mTBI模型，并评估野生型小鼠的长期病理和认知变化。我们将使小鼠暴露在间隔数天或数周的多次重复的皮质撞击中，并研究这些损伤的长期后果。最重要的是，我们将在最初的创伤冲击发生几天、几周或几个月后，用神经再生蛋白疗法来治疗这些受损的小鼠。在完成拟议的研究后，我们期望有临床前的证据证明CSF1和/或IL-34在减轻mTBI小鼠模型的病理和缓解症状方面的有效性。由于CSF1在临床上用于人类，我们的研究结果可能会迅速转化为临床。

DESCRIPTION (provided by applicant): In recent war-related conflicts, traumatic brain injury (TBI) has become a signature injury affecting a large percentage of the Veteran population. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for approximately 70-80% of all TBI among returning Veterans as well as the civilian population. Although most overt symptoms of mTBI resolve spontaneously within days or weeks of the injury, in 10-20% of mTBI victims some functional deficits persist, with recent estimates suggesting that as many as 44-50% of mTBI patients experience three or more symptoms at one-year post-injury. Repetitive mTBI is of particular interest because military personnel often have several mTBI exposures over the course of their lives and possibly within single deployments. Recurrent brain injuries, even when mild, may interfere with neuropsychological recovery. Repeated concussion has also been associated with chronic traumatic encephalopathy (CTE), a neurodegenerative disorder with progressive impairments of memory and cognition, as well as depression, anxiety, and motor abnormalities. Among the proposed environmental risk factors of neurodegenerative disease, TBI, including mild TBI, is probably one of the most consistent candidates for initiating the molecular cascades and provoking neurodegeneration leading to Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis. Consequently TBI has been shown to accelerate pathology and behavioral deficits in genetic models of AD or to enhance vulnerability to Parkinsonism-inducing neurotoxins. Recent evidence also identified TBI as an environmental risk factor of frontotemporal dementia (FTD), an early onset dementia associated in its behavioral variant with behavioral abnormalities, loss of sociability, or impulsive and irrational behavior. Our preliminary studies show that mild repetitive impacts to the head of mice using a controlled impactor (closed head injury) result in gliosis, white matter changes, and cognitive deficits 3 months after injury. Separately, we showed that macrophage colony-stimulating factor (CSF1), a key growth factor in the hematopoietic system, has prominent neuroprotective effects in acute brain injury when administered systemically after injury. These effects are mediated via CSF1 receptor (CSF1R) expressed at least in part by injured neurons. A newly discovered second ligand for this receptor, IL-34, seems to be equally or more potent than CSF1 in our model. Most importantly, for this proposal, preliminary studies show a remarkable recovery of memory impairment and reduced gliosis with a single bolus treatment of CSF1 after injury in our model of mTBI. Based on these preliminary data we hypothesize that mild traumatic insults to the central nervous system lead to long-term neurobehavioral deficits in mice which model in part the deficits observed in human mTBI patients, and that systemic treatment with CSF1 and IL-34 will attenuate brain injury and related behavioral deficits even if given days or weeks after injury. In this application we propose to refine our model of mTBI and assess long-term pathological and cognitive changes in wildtype mice. We will expose mice to multiple repetitive cortical impacts that are days or weeks apart and study the longterm consequences of these injuries. Most importantly, we will treat such impaired mice with neuroregenerative protein therapies days, weeks or months after the initial traumatic impact occurred. After completion of the proposed studies we expect to have preclinical proof for efficacy of CSF1 and/or IL-34 in reducing pathology and alleviating symptoms in mouse models of mTBI. Since CSF1 is used clinically in humans our findings may find rapid translation to the clinic.