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: 10810929
• 负责人: LI-RU ZHAO
• 金额: $ 3.91万
• 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/10810929
• 关键词: Acute; Affect; Bone Marrow; Brain; Brain Injuries; Brain imaging; Cancer Patient; Caring; Cerebrum; Chronic; Chronic Phase; Cognition; Colony-Stimulating Factors; Combined Modality Therapy; Country; Cre-LoxP; Data; Demyelinations; Dependence; Development; Emotional; Evaluation; Event; FDA approved; Family; Financial Hardship; Future; Generations; Goals; Growth Factor; Health; Hematopoietic Cell Growth Factors; Individual; Injury; Ipsilateral; Learning; Life; Long-Term Care; Longevity; Macrophage; 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; Proliferating; 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; brain repair; care costs; chemotherapy; disability; economic cost; efficacy evaluation; enhancing factor; evidence base; exosome; functional improvement; improved; monocyte; neural; neurobehavioral; novel; oligodendrocyte progenitor; pharmacologic; preclinical study; productivity loss; psychologic; recruit; remyelination; repaired; stem cell biology; 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）是美国的一场公共卫生危机。 TBI 是一种非常常见的损伤 在年轻人中，会导致认知、学习和记忆、情绪控制等方面的长期障碍 感觉和运动功能。严重的 TBI 可能会导致终生的身体和心理问题 增加患神经退行性疾病的风险。年轻人中严重的 TBI 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，而且还会造成 美国经济负担沉重。 在传统观点中，TBI 是一种只需要紧急处理和短期康复的事件。 今天的观点是，TBI 是一种慢性健康状况的发作，需要治疗来改善 TBI 后数月甚至数年的恢复。然而，在慢性期没有这样的治疗方法。这 慢性期存在于TBI后3或6个月的较长时期内，并贯穿个体的一生。这 缺乏改善严重 TBI 慢性期康复的治疗方法是该国面临的一个关键问题。 在年轻的成年小鼠中使用严重的 TBI 模型，我们已经证明了功能的显着改善 通过干细胞因子（SCF）和粒细胞集落刺激因子（G- CSF) (SCF+G-CSF) 处于慢性期。然而，目前尚不清楚 SCF+G-CSF 治疗如何在 严重 TBI 的慢性期可改善功能恢复。该应用程序的目的是确定 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 恢复是由 增强脑髓鞘再生和神经结构再生。使用分子方法 和细胞生物学、药理学、Cre-LoxP 技术、2 光子活体脑成像和神经行为 评估中，该假设将通过两个具体目标进行检验。目标 1 将确定 SCF+G-CSF 如何 严重 TBI 慢性期的治疗可增强脑白质的髓鞘再生，目标 2 将 定义严重 TBI 慢性期 SCF+G-CSF 治疗如何增强神经结构再生。 寻找改善慢性期严重 TBI 恢复的治疗方法是一个非常重要但并非如此的问题。 调查领域和国家迫切需要改善患有严重 TBI 的年轻人的健康。它 预计所提出的机制研究的完成将显着推动 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，从而推动研究领域向前发展 处于慢性期。