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

探索 SCF G-CSF 增强慢性 TBI 恢复的机制。

• 批准号: 10376341
• 负责人: LI-RU ZHAO
• 金额: $ 41.06万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376341
• 关键词: Acute; Affect; Bone Marrow; Brain; Brain Injuries; Brain imaging; Cancer Patient; Caring; Cerebrum; Chronic; Chronic Phase; Cognition; Country; Cre-LoxP; Data; Demyelinations; Dependence; Development; Emotional; Evaluation; Event; FDA approved; Family; Financial Hardship; Future; Generations; Goals; Granulocyte Colony-Stimulating Factor; Growth Factor; Health; Hematopoietic Cell Growth Factors; Individual; Injury; Ipsilateral; Lead; Learning; Life; Long-Term Care; Longevity; Mediating; Medical; Medical Care Costs; Memory; Modeling; Molecular; Molecular Biology; Molecular and Cellular Biology; Motor; Mus; Natural regeneration; Neurites; Neurodegenerative Disorders; Oligodendroglia; Operative Surgical Procedures; Pathology; Pharmacology; Physical therapy; Public Health; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Risk; Sensory; Stem Cell Factor; Stroke; Structure; Survivors; TBI treatment; Technology; Testing; Therapeutic; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Factor; United States; Work; base; brain repair; care costs; chemotherapy; disability; economic cost; efficacy evaluation; enhancing factor; evidence base; exosome; functional improvement; functional outcomes; improved; macrophage; monocyte; neurobehavioral; novel; oligodendrocyte progenitor; preclinical study; productivity loss; psychologic; recruit; relating to nervous system; remyelination; repaired; stem cell biology; stem cell therapy; stem cells; two-photon; white matter; young adult

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.

摘要/摘要 创伤性脑损伤（TBI）代表着美国的公共卫生危机。 TBI是非常常见的伤害 在年轻人中，在认知，学习和记忆，情感控制和 感觉和运动功能。严重的TBI会导致终生的身体和心理问题，并且 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 健康问题和民族烧伤，因为他们的终生疾病，永久生产力丧失和长期 术语日常护理依赖不仅会严重影响个人及其家人的生活，而且还会产生一个 美国的财务燃烧大量燃烧。 从传统观点看，TBI是一个只需要急性管理和短暂康复的事件。 今天的想法是，TBI是需要改善疗法的慢性健康状况的开始 TBI恢复几个月和几年。但是，在慢性阶段没有这种治疗方法。这 长期存在于TBI后3到6个月的长期存在，整个人的寿命。这 缺乏治疗以改善慢性阶段的严重TBI恢复是该国的关键问题。 在年轻的成年小鼠中使用严重的TBI模型，我们显示出功能的显着改善 通过对干细胞因子（SCF）和粒细胞群刺激因子的组合恢复（g-） CSF（SCF+G-CSF）在慢性阶段。但是，尚不清楚SCF+G-CSF如何处理 严重TBI的慢性期改善了功能恢复。此应用的目的是确定 慢性TBI中SCF+G-CSF增强恢复的基本机制。基于初步研究， 我们假设SCF+G-CSF改良的重度TBI在慢性阶段介导 大脑透明度和神经结构再生的增强。使用分子的方法 和细胞生物学，药理学，Cre-loxp技术，2-Photon Live Brain Imaging和Neurobehavioral 评估，该假设将通过两个具体目标进行检验。 AIM 1将确定SCF+G-CSF如何 严重TBI的慢性阶段的治疗增强了脑白质中的再生，AIM 2将 定义在严重TBI的慢性阶段中SCF+G-CSF如何增强神经元结构再生。 寻找治疗方法以改善慢性阶段的严重TBI恢复是一种高度重要但不是 调查了领域，并紧急的国家要求改善严重TBI的年轻人的健康状况。它 预计提出的机械研究的实现将显着移动TBI 通过识别一种独特的药物修复严重的TBI损害大脑的方法来向前发展。 在慢性阶段。