Reinforcing the Repair Response to Traumatic Brain Injury

加强对创伤性脑损伤的修复反应

• 批准号: 9280774
• 负责人: Shijie Song
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280774
• 关键词: Affect; Afghanistan; Alternative Splicing; Animal Experiments; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Astrocytes; Astrocytosis; Atrial Natriuretic Factor; Attenuated; Behavior; Behavior assessment; Behavioral; Biochemical Process; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Injuries; Brain Stem; Brain natriuretic peptide; Brain region; Brain-Derived Neurotrophic Factor; CSF3 gene; Cell Culture Techniques; Cell Death; Cells; Cerebrovascular system; Chronic; Clinical Research; Complex; Contralateral; Devices; Dose; Endothelial Cells; Ensure; GDNF gene; Generations; Goals; Granulocyte Colony-Stimulating Factor; Green Fluorescent Proteins; Growth Factor; Hippocampus (Brain); Hour; Immunofluorescence Immunologic; Infiltration; Injury; Investigation; Ipsilateral; Iraq; Knock-out; Label; Lesion; Leukocytes; Light; Measures; Mediating; Mediation; Methods; Microglia; Military Personnel; Molecular; Molecular Analysis; Motor; Mus; Neuraxis; Neuroimmune system; Neurologic; Neurologic Deficit; Neurons; Operative Surgical Procedures; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Prevention; Procedures; Process; Receptor Cell; Recording of previous events; Recovery; Regenerative response; Reporting; Research; Rodent Model; Role; Rotarod Performance Test; Signal Pathway; Signal Transduction; Stem cells; Stroke; Subarachnoid Hemorrhage; Survivors; Terrorism; Testing; Time; Tissue Sample; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Up-Regulation; Vascular Endothelial Cell; Water; Whole-Body Irradiation; angiogenesis; brain cell; brain repair; brain tissue; chemokine; chemokine receptor; controlled cortical impact; cytokine; design; disability; high risk; injured; intravenous administration; monocyte; monocyte chemoattractant protein 1 receptor; motor deficit; mouse model; nerve stem cell; neurogenesis; neuroinflammation; neurological recovery; neuron apoptosis; neuron loss; neuronal survival; neurotransmission; neurotrophic factor; novel strategies; programs; public health relevance; receptor; regenerative; repaired; response; standard care; vasogenic edema

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a complex process encompassing three overlapping phases: a) primary injury, b) secondary injury and c) regenerative responses. Systemic administration of granulocyte-colony stimulating factor (G-CSF) represents a novel approach for reinforcing the brain's self-repair, especially during the secondary and regenerative phases. The Specific Aims of this research program are designed to test the hypotheses that a) G-CSF indirectly enhances brain repair by promoting infiltration of bone marrow-derived cells (BMDC) to brain, modulate neuro-inflammatory processes and secrete trophic factors; b) G-CSF directly interacts with its neural cells receptors to trigger intra-cellular signaling cascades that decrease cell death and promote neurogenesis. Aim 1 will determine the optimal dose of G-CSF and the recovery time-course of behavioral deficits after TBI in mice. Non-irradiated mice will be used to ensure the effects of G-CSF are not confounded by whole body irradiation and bone marrow transplantation (BMT). Motoric function (biased swing activity; rotarod) and behavioral (water maze) end-points will be assessed in mice at baseline, 3, 7, and 14 days after TBI. Secondary endpoints will measure a) lesion volume, b) extent of microgliosis and astrocytosis and c) brain regional levels of cytokines. Aim 2a. To assess the extent of BMDC mobilization triggered by TBI and modulated by G-CSF, the phenotypic fate and distribution of green fluorescent protein (GFP+) BMDC in chimeric mice brains will be determined using immunofluorescence to identify microglia, astrocytes, and neuron-like cells that co-express GFP. The time-course of infiltration of GFP+ BMDCs will be determined by assessing total GFP+ burden ipsilateral and contralateral to the TBI at 3, 7 and 14 days after injury. Aim 2b. To determine the extent to which BMDC penetration into brain is responsible for enhanced TBI recovery, the infiltration of BMDC into the central nervous system (CNS) will be attenuated or blocked with agents that block chemokine signaling to monocytes or utilization of mice with a knockout of the chemokine receptor CCR2. Enhanced recovery despite inhibition of BMDC mobilization will support the hypothesis that direct actions of G-CSF on neural cells play a major role. Aim 3. To investigate the direct effects of G-CSF action on neural cells, the molecular impact of these cytokines on signal transduction, apoptosis and neurogenesis will be assessed in neural cell cultures. Results from this analysis will be compared to molecular analyses of signal transduction and anti- apoptosis in tissue samples dissected from TBI brains treated with G-CSF or vehicle. Methods: Chimeric mice will be generated that harbor GFP BMDCs to permit tracking the distribution and phenotypic fate of BMDCs that infiltrate the brain after TBI. Surgery: TBI will be delivered with a pneumatically driven controlled cortical impact (CCI) device to mice. Behavioral Assessments: Analyses of motor asymmetry (EBST), rotarod test and Water Maze (MWM). Endpoints: a) changes in behavior; b) changes in lesion volume; c) extent, distribution and phenotypic fate of GFP+ BMDC in brain assessed by double-labeling procedures; d) changes in cytokine profiles in brain regions; e) changes in signal transduction (PKC-�), Bcl2. Expected Results: G-CSF will modulate BMDCs infiltration and enhance recovery of behavioral deficits. Improvement of neurologic deficits will shown to be related to a combination of actions including a) changes in brain infiltration of BMDC; b) secretion of cytokines that promote neurogenesis; c) up-regulation of anti-apoptotic signaling triggered by G-CSF acting directly on its receptor in neural cells.

描述（由申请人提供）：

项目成果

Hippocampal neurogenesis and the brain repair response to brief stereotaxic insertion of a microneedle.

• DOI: 10.1155/2013/205878
• 发表时间: 2013
• 期刊: Stem cells international
• 影响因子: 4.3
• 作者: Song S;Song S;Cao C;Lin X;Li K;Sava V;Sanchez-Ramos J
• 通讯作者: Sanchez-Ramos J

Detrimental effects of physical inactivity on neurogenesis.

缺乏身体活动对神经发生的不利影响。

• DOI: 10.4103/2394-8108.186278
• 发表时间: 2016-04
• 期刊: Brain circulation
• 影响因子: 1.9
• 作者: Lippert T;Watson N;Ji X;Yasuhara T;Date I;Kaneko Y;Tajiri N;Borlongan CV
• 通讯作者: Borlongan CV

Transient Microneedle Insertion into Hippocampus Triggers Neurogenesis and Decreases Amyloid Burden in a Mouse Model of Alzheimer's Disease.

瞬时微针插入海马体可触发阿尔茨海默病小鼠模型中的神经发生并减少淀粉样蛋白负担。

• DOI: 10.3727/096368916x691114
• 发表时间: 2016
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Song,Shijie;Kong,Xiaoyung;Sava,Vasyl;Cao,Chuanhai;Acosta,Sandra;Borlongan,Cesar;Sanchez-Ramos,Juan
• 通讯作者: Sanchez-Ramos,Juan