Brain Repair by Hematopoietic Growth Factors in Traumatic Brain Injury

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 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.