Brain Repair by Hematopoietic Growth Factors in Traumatic Brain Injury

 产品说明： 创伤性脑损伤（TBI）是伊拉克和阿富汗战争中的一种标志性损伤。TBI导致严重的持续性残疾，包括认知障碍和心理健康问题，导致从战争中返回的年轻退伍军人的生产力和生活质量下降。与战斗有关的TBI的长期医疗保健费用造成了巨大的财政负担，并在美国产生了严重的公共和个人危机。到目前为止，基于证据的治疗TBI恢复还没有。考虑到TBI退伍军人目前处于疾病的慢性期，迫切需要开发TBI慢性期脑修复的神经恢复策略。 我们最近的研究表明，在慢性期，通过两种必需的造血生长因子，干细胞因子（SCF）和粒细胞集落刺激因子（G-CSF）（SCF+G-CSF）的组合，脑卒中损伤是可修复的。使用相同的方法，我们的初步研究已经证明了SCF+G-CSF在TBI慢性期脑修复中的神经恢复功效。然而，目前尚不清楚SCF+G-CSF如何修复TBI慢性期的大脑，以及SCF+G-CSF治疗是否可以修复延迟慢性期的TBI损伤的大脑。本研究计划的目的是解决这些悬而未决的问题。基于我们最近的出版物和初步数据，我们假设SCF+G-CSF通过神经网络重新布线来修复TBI慢性期的大脑，这是通过其对神经元的直接调节和其通过骨髓来源的单核细胞/巨噬细胞（BMDM）的间接作用来实现的。使用活体脑成像、转基因小鼠和靶向敲除小鼠、神经行为评估和细胞信号传导的方法，将测试中心假设，并且通过实现以下3个具体目标来实现本申请的目的：目的1将确定SCF+G-CSF在TBI的延迟慢性期中对脑修复的贡献，目的2将确定神经网络重新布线在SCF+G-CSF诱导的慢性TBI脑修复中的作用，目的3将确定BMDM在SCF+G-CSF诱导的慢性TBI脑修复中的参与。 本项目创新性地提出了利用造血生长因子修复慢性TBI脑损伤的独特方法，这是我们团队独创的。这项研究将显着推进目前的知识在康复研究TBI。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TBI修复中神经可塑性治疗策略的发展。这项研究的贡献是符合退伍军人管理局的使命，以确保退伍军人实现最大限度地恢复战斗相关的神经创伤。

 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.