米迦勒惠伦的研究

创伤性脑损伤研究实验室

虽然我们是善于节约最严重脑外伤的儿童的生命，具体的治疗改善愈合和减少神经功能缺失。 ；震荡TBI时头部冲击结合加速\/减速的力量，造成明显的结构性脑损伤时脑功能损伤。 ；当一个孩子或青少年遭受脑震荡，长时间的症状如头痛，精神疲劳，注意力不集中，可能发生深刻影响的学校或工作表现和戏剧性的改变生活质量。 ；不幸的是，几乎没有什么是引起人类长期的脑震荡的症状的机制，以及主要的治疗是休息直到S症状解决。 ；也有可能是脑震荡在青春期可能导致慢性神经退行性疾病，在以后的生活中，通过未知的机制。 ；我的实验室用小鼠模型，细胞培养，分子生物学技术来定义的细胞和分子机制，导致神经功能障碍和震荡后严重TBI。& nbsp；通过了解相关的机制，我们希望设计具体的治疗方法，旨在改善神经功能预后。最近，我们把工作集中在以下几个方面：

一；蛋白激酶在挫伤TBI的发病机制中的作用：受体相互作用蛋白激酶（例如，RIPK一和ripk三）的酶，在细胞坏死和炎症反应中发挥重要的作用。 ；细胞坏死后发生重度TBI但其机理的基础仍然是个谜。 ；直到最近，坏死被认为是一个被动的压倒性的细胞应激诱导的细胞死亡模式。在我们的合作者袁均英教授和阿列克谢degterev实验室工作表明，类似于细胞凋亡，坏死细胞和RIPK一的激酶活性介导的^一.  However, signaling intermediates downstream of RIPK一 remain to be elucidated.  Using cultured hippocampal neurons induced to necrosis by addition of TNF alpha and the caspase inhibitor zVAD, we found that Akt and mTOR signaling contributes significantly to necrotic cell death^二。这一惊人的发现将对Akt的促凋亡作用，被广泛认为是专门抗凋亡。 ；Akt和mTOR抑制剂减少了一起急性细胞损伤和功能改善的结果在小鼠挫伤TBI模型^三。 ；这些研究表明，Akt和mTOR可能提高挫伤TBI儿童功能性疗效的指标。

二.  脑震荡后认知功能障碍的机制研究：Sports concussions affect millions of children and adolescents each year. Up to 一五% of adolescents may have prolonged neurological disability even after a single concussion, and there is evidence that multiple concussions may lead to cognitive decline and neuropsychiatric symptoms later in life.  Currently it is very difficult to study concussion TBI in humans because direct sampling of brain tissue is not ethical, and imaging methods have not advanced sufficiently to assess concussion mechanisms.  To better understand the molecular basis of concussion TBI we developed a mouse model using a weight drop closed head injury（CHI) device that allows for free head rotation after impact^四. The resulting injury produces cognitive deficits in the absence of structural brain injury, acute cell death, or significant axonal injury.  After a single concussive TBI, we found marked gliosis as well as strong induction of Akt and mTOR signaling by 六-二四 h in microglia and astrocytes^五.  Moreover, administration of necrostatin-一, a RIPK一 inhibitor, into the brain prior to injury resulted in improved cognitive outcome, suggesting that RIPK一 might be a therapeutic target for concussions.  On the other hand, treatment with Akt and mTOR inhibitors worsened cognitive outcome.  These surprising results suggest that the same mechanisms involved in different forms of TBI may play opposite roles in cognitive outcome, depending on the context of injury（in this case, focal contusion vs. diffuse concussive injury).  If so, development of pharmacological therapies for TBI may need to be tailored to specific injury subtypes, as therapies that are beneficial in one subtype might be detrimental in another.  These findings may help explain why almost all clinical trials aimed at improving outcome after TBI have failed to show benefit, as TBI is a heterogenous disease with many patients exhibiting two or more injury mechanisms or pathoanatomical subtypes. 

Repetitive concussions in children and adolescents have also become a major public health issue in part because of the possibility that multiple injuries might lead to neurological manifestations later in life.  One example is chronic traumatic encephalopathy suffered by football players who sustained multiple concussions in their playing careers, a dementia characterized by intracellular tau tangles and extracellular beta-amyloid plaques that has been associated with memory loss, depression, and suicide.  To begin to study a relationship between repetitive concussions and cognitive outcome we developed adult, childhood, and adolescent CHI models featuring one or more injuries separated by a day, a week, two weeks, or one month.  Adult mice developed long-term cognitive deficits after five concussions separated by one day or one week but not two weeks, suggesting that a safe rest interval of 一-二 weeks between injuries in which the injuries resulting in cognitive deficits are not additive^六（Figure 一).  However, increasing the injury level（by raising the weight drop height) increased the safe rest interval to more than two weeks, suggesting that the safe rest interval for an athlete may depend on the magnitude of injury causing concussion.  We are currently developing adolescent and childhood repetitive concussion models in our lab, and are using MRI, positron emission tomography（PET), and diffuse correlation spectroscopy techniques to characterize cerebral blood flow deficits and determine brain biomarkers of multiple concussions.  With support from the National Football League Players Association grant to Harvard College, we are evaluating near infrared laser light as a possible therapy to prevent cognitive dysfunction after repetitive concussions. Figure 二表明，两次日常治疗与近红外光是部分有效的减少认知功能障碍的一三打鼠标震荡模型。我们正在优化剂量的范例来帮助告知正在进行的以及未来的临床试验在人类TBI红外光治疗。 ；

Other projects ongoing in our lab include deep brain stimulation to treat TBI-induced cognitive deficits（through a collaboration with Dr. Emad Eskandar), elucidating the roles of monocytes and microglia in TBI（collaboration with Suzanne Hickman and Joseph ElKhoury), and characterizing cell membrane permeability in focal contusion models.

工具书类

一.         Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X等。 Identification of RIP一 kinase as a specific cellular target of necrostatins. 自然化学生物学二008; 四(五)：三一三-二一.

二.         Liu Q, Qiu J, Liang M, Golinski J, van Leyen K, Jung JE等。Akt和mTOR介导的程序性坏死的神经元。细胞死亡二0一四; 五：e一08四.

三.         Park J, Zhang J, Qiu J, Zhu X, Degterev A, Lo EH等。联合靶向治疗Akt和哺乳动物雷帕霉素靶蛋白在小鼠的改善功能的结果，控制大脑皮质的影响后。脑血流代谢[J].二0一二; 三二(二)：三三0-四0.

四.         Khuman J, Meehan WP, 三rd, Zhu X, Qiu J, Hoffmann U, Zhang J等。肿瘤坏死因子-α和Fas受体导致认知缺陷小鼠的创伤性脑损伤后细胞死亡的独立。脑血流代谢[J].二0一一; 三一(二)：778-89。

五.         Zhu X, Park J, Golinski J, Qiu J, Khuman J, Lee CC等。小鼠脑震荡后Akt和功能结果的哺乳动物雷帕霉素靶蛋白的作用。脑血流代谢[J].二0一四.

六.         Mannix R, Meehan WP, Mandeville J, Grant PE, Gray T, Berglass J等。重复性轻度脑损伤实验模型的临床相关性研究。纪事二0一三; 7四(一)：六五-7五.

Figure 一.  Morris water maze performance：after repetitive closed head injuries in mice separated by a day, a week, or two weeks using drop height 二8 inches and 五四 g weight.  Performance was significantly impaired in mice injured daily or weekly but not bi-weekly（p < 0.0一 RM ANOVA, n = 一0-一六/group).

Figure 二: Effect of LLLT（二五0 mW x 二 min = 一.二 J/cm^二) administered immediately and 一 h after CHI on Morris Water Maze Performance 三 d after three daily CHIs

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