Brain Repair by Hematopoietic Growth Factors in Traumatic Brain Injury

 说明： 摘要创伤性脑损伤是伊拉克和阿富汗战争中的一种标志性损伤。脑外伤导致严重的永久性残疾，包括认知障碍和心理健康问题，导致从战争归来的年轻退伍军人失去生产力和生活质量。与战斗有关的TBI的长期医疗费用造成了巨大的财政负担，并在美国引发了严重的公共和个人危机。到目前为止，还没有针对创伤性脑损伤恢复的循证治疗。考虑到脑外伤退伍军人目前处于疾病的慢性期，迫切需要制定脑损伤慢性期的神经修复策略。我们最近的研究表明，在两种基本的造血生长因子-干细胞因子(SCF)和粒细胞集落刺激因子(G-CSF)(SCF+G-CSF)的联合作用下，中风损伤的脑在慢性期是可以修复的。用同样的方法，我们的初步研究证明了SCF+G-CSF在脑损伤慢性期的神经修复效果。然而，目前尚不清楚SCF+G-CSF如何修复颅脑损伤慢性期的大脑，以及SCF+G-CSF治疗是否能修复延迟慢性期的脑损伤。这项研究提案的目的是解决这些悬而未决的问题。根据我们最近的文献和初步数据，我们假设SCF+G-CSF通过神经网络重连修复处于慢性脑损伤阶段的大脑，这是通过其对神经元的直接调节和通过骨髓来源的单核/巨噬细胞(BMDM)的间接作用实现的。利用活体脑成像、转基因小鼠和靶向敲除小鼠、神经行为评估和细胞信号转导等方法，将检验中心假设，并通过实现以下三个具体目标来实现这一应用的目的：目的1确定SCF+G-CSF在迟发性脑损伤慢性期脑修复中的作用，目的2确定神经网络重连在SCF+G-CSF诱导的慢性脑损伤脑修复中的作用，目的3确定BMDM参与SCF+G-CSF诱导的慢性脑损伤脑修复。本项目在本课题组独创的慢性脑损伤中使用造血生长因子修复脑损伤的独特方法上具有创新性。这项研究将极大地促进目前对颅脑损伤康复研究的认识。这项研究与RR&D优先领域的目标和范围高度一致，以支持慢性脑外伤修复中神经可塑性治疗策略的发展。这项研究的贡献与退伍军人管理局的使命是一致的，以确保退伍军人从与战斗有关的神经创伤中实现最大限度的恢复。

 DESCRIPTION: Abstract Traumatic brain injury (TBI) represents a signature injury of the Iraq and Afghanistan conflicts. TBI causes severe persistent disability including cognitive impairment and mental health problems, resulting in loss of productivity and quality of life for the young Veterans returning from the wars. The long-term health care costs of combat-related TBI have created a huge financial burden and generated serious public and personal crises in the United States. To date, evidence-based treatment for TBI recovery is not yet available. Considering the fact that TBI Veterans are currently in the chronic phase of the disease, there is a critical need to develop neurorestorative strategies for brain repair in the chronic phase of TBI. Our recent studies have revealed that a stroke-damaged brain is repairable in the chronic phase by the combination of two essential hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF). Using the same approach, our preliminary studies have demonstrated the neurorestorative efficacy of SCF+G-CSF in brain repair in the chronic phase of TBI. However, it remains unclear how SCF+G-CSF repairs the brain in the chronic phase of TBI and whether SCF+G-CSF treatment could repair a TBI-damaged brain in a delayed chronic phase. The objective of this research proposal is to address these unanswered questions. Based on our recent publications and preliminary data, we hypothesize that SCF+G-CSF repairs a brain in the chronic phase of TBI through neural network rewiring, which is accomplished by its direct regulation of neurons and its indirect effects via bone marrow-derived monocytes/macrophages (BMDM). Using the approaches of live brain imaging, transgenic mice and targeted knockout mice, neurobehavioral assessments, and cell signaling, the central hypothesis will be tested and the objective of this application wil be achieved by accomplishing the following 3 specific aims: Aim 1 will determine the contribution of SCF+G-CSF on brain repair in the delayed chronic phase of TBI, Aim 2 will define the role of neural network rewiring in SCF+G-CSF-induced brain repair in chronic TBI, and Aim 3 will identify the involvement of BMDM in SCF+G-CSF-induced brain repair in chronic TBI. This project is innovative in the unique approach of using hematopoietic growth factors to repair the brain in chronic TBI, which is originally created by our group. This study will significantly advance current knowledge in rehabilitation research for TBI. This research is highly compatible with the objective and scope of the RR&D priority areas for supporting the development of therapeutic strategies on neural plasticity in chronic TBI repair. The contribution of this research is in keeping with the VA mission to ensure that Veterans achieve maximal recovery from combat-related neurotrauma.