Exploring mechanisms underlying SCF+G-CSF-enhanced recovery in chronicTBI.

总结/摘要 创伤性脑损伤（TBI）是美国的公共卫生危机。TBI是一种非常常见的损伤 在年轻人中，并导致认知、学习和记忆、情绪控制方面的长期残疾， 感觉和运动功能。严重的TBI可能导致终身的身体和心理问题， 增加患神经退行性疾病的风险。年轻人的严重TBI是一个重要的公众问题。 健康问题和国家负担，因为他们终身残疾、永久丧失生产力和长期 长期的日常护理依赖不仅严重影响个人及其家庭的生活， 美国的沉重财政负担。 传统观点认为，TBI是一种只需急性处理和短期康复的事件。 今天的观念是，TBI是一种慢性健康状况的开始，需要治疗来改善 在TBI后数月和数年恢复。然而，在慢性期没有这样的治疗方法。的 慢性期存在于TBI后3或6个月的长时间内，并贯穿个体的整个寿命。的 缺乏治疗以改善慢性期严重创伤性脑损伤的恢复是该国的一个关键问题。 使用年轻成年小鼠的严重TBI模型，我们已经证明了功能的显著改善， 通过干细胞因子（SCF）和粒细胞集落刺激因子（G- CSF）（SCF+G-CSF）。然而，目前尚不清楚SCF+G-CSF治疗如何在 严重TBI的慢性期改善功能恢复。本申请的目的是确定 SCF+G-CSF增强慢性TBI恢复的潜在机制。根据初步研究， 我们假设SCF+G-CSF改善慢性期严重TBI的恢复是由 促进脑髓鞘再生和神经结构再生。利用分子生物学的方法 细胞生物学、药理学、Cre-LoxP技术、双光子活体脑成像和神经行为学 评估，这一假设将通过两个具体目标进行测试。目的1将确定SCF+G-CSF 在严重TBI慢性期的治疗增强了大脑白色物质的髓鞘再生，Aim 2将 定义SCF+G-CSF治疗在严重TBI慢性期如何增强神经结构再生。 寻找治疗方法来改善慢性期严重TBI的恢复是一个非常重要的，但不是， 调查领域和迫切的国家需求，以改善健康的年轻成年人生活与严重的TBI。它 预计拟议的机制研究的完成将大大推动TBI 通过确定一种独特的药理学方法来修复严重TBI损伤的大脑， 在慢性阶段。

SUMMARY/ABSTRACT Traumatic brain injury (TBI) represents a public health crisis in the United States. TBI is a very common injury in young adults and causes long-term disabilities in cognition, learning and memory, emotional control, and sensory and motor function. A severe TBI can lead to lifelong physical and psychological problems and increase the risk of developing neurodegenerative diseases. Severe TBI in young adults is a significant public health problem and national burden because their lifelong disabilities, permanent productivity loss, and long- term daily care dependence not only seriously affect the life of an individual and their family but also create a heavy financial burden in the United States. In the traditional view, TBI is an event that only needs acute management and a brief period of rehabilitation. Today’s notion is that TBI is the onset of a chronic health condition that requires therapies for improving recovery months and years after TBI. However, no such a treatment is available in the chronic phase. The chronic phase exists in a long period from 3 or 6 months after TBI and throughout an individual’s life span. The lack of treatment to improve severe TBI recovery in the chronic phase is a critical problem for the country. Using a severe TBI model in young adult mice, we have demonstrated significant improvements in functional recovery by a combination treatment of stem cell factor (SCF) and granulocyte colony-stimulating factor (G- CSF) (SCF+G-CSF) in the chronic phase. However, it remains unclear how SCF+G-CSF treatment in the chronic phase of severe TBI improves functional recovery. The objective of this application is to determine the underlying mechanisms of the SCF+G-CSF-enhanced recovery in chronic TBI. Based on preliminary studies, we hypothesize that SCF+G-CSF-improved severe TBI recovery in the chronic phase is mediated by the enhancement of cerebral remyelination and neurostructural regeneration. Using the approaches of molecular and cellular biology, pharmacology, Cre-LoxP technology, 2-photon live brain imaging and neurobehavioral evaluation, this hypothesis will be tested through two Specific Aims. Aim 1 will determine how SCF+G-CSF treatment in the chronic phase of severe TBI enhances remyelination in cerebral white matter, and Aim 2 will define how SCF+G-CSF treatment in the chronic phase of severe TBI enhances neural structure regeneration. Searching for treatments to improve severe TBI recovery in the chronic phase is a highly-important-but-not- investigated field and an urgent national demand to improve the health of young adults living with severe TBI. It is expected that the accomplishment of the proposed mechanistic studies will significantly move the TBI research field forward by identifying a unique pharmacological approach to repair a severe TBI-damaged brain in the chronic phase.