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

探索 SCF G-CSF 增强慢性 TBI 恢复的潜在机制。

• 批准号: 10220357
• 负责人: LI-RU ZHAO
• 金额: $ 40.52万
• 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/10220357
• 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/文摘