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

摘要/摘要 创伤性脑损伤在美国代表着一种公共健康危机。颅脑损伤是一种非常常见的损伤 并导致长期的认知、学习和记忆、情绪控制和 感觉和运动功能。严重的脑外伤会导致终生的生理和心理问题， 增加患神经退行性疾病的风险。年轻人中的严重脑外伤是一个重要的公众 健康问题和国家负担，因为他们终身残疾，永久性生产力丧失，以及长期- 长期的日常护理依赖不仅严重影响个人及其家庭的生活，而且还会造成 美国的财政负担很重。 在传统观念中，脑损伤是一种只需要急诊处理和短暂的康复期的事件。 今天的概念是，脑外伤是一种慢性健康状况的开始，需要通过治疗来改善 颅脑损伤后数月和数年恢复。然而，在慢性期没有这样的治疗方法。这个 慢性期存在于颅脑损伤后3个月或6个月的很长一段时间内，贯穿于个体的整个生命周期。这个 在慢性阶段，缺乏治疗来改善严重的脑损伤恢复是该国的一个关键问题。 在年轻成年小鼠中使用严重的脑外伤模型，我们已经证明在功能上有显著的改善。 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是如何治疗 重型颅脑损伤慢性期可促进功能恢复。此应用程序的目标是确定 干细胞因子-粒细胞集落刺激因子促进慢性脑损伤恢复的机制根据初步研究， 我们推测，SCF-G-CSF改善慢性期重重型颅脑损伤的恢复是通过 促进脑髓鞘再生和神经结构再生。运用分子生物学的方法 以及细胞生物学、药理学、CRE-loxP技术、双光子脑成像和神经行为学 评估，这一假设将通过两个具体的目标进行检验。目标1将确定干细胞因子G-CSF如何 重型颅脑损伤慢性期的治疗可促进脑白质重新髓鞘形成，Aim 2将 明确SCF-G-CSF在重型颅脑损伤慢性期的治疗如何促进神经结构再生。 寻找治疗方法来改善慢性重型颅脑损伤的恢复是非常重要的-但不是- 调查领域和国家对改善患有严重脑外伤的年轻人的健康的迫切需求。它 预计拟议的机械学研究的完成将大大推动TBI 通过确定修复严重脑损伤的独特药理学方法推进研究领域 处于慢性期。

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.