Adult Neurogenesis after Stroke: The role of SDF-1 in mechanisms of neural repair

成人中风后神经发生：SDF-1 在神经修复机制中的作用

• 批准号: 8325084
• 负责人: Tahir Ahmed
• 金额: $ 4.72万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2016-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325084
• 关键词: Acute; Adult; Apoptotic; Area; Binding; Biological; Blood; Brain; Brain Ischemia; CXC chemokine receptor 3; CXCR3 gene; CXCR4 gene; Cause of Death; Cell Death; Cell Death Process; Cell Maturation; Cell Survival; Cells; Chronic; Chronic Phase; Cleaved cell; Cognitive deficits; Coupled; Development; Embryo; Environment; Glucose; Growth Factor; Immigration; Immune; Immune response; Impaired cognition; In Vitro; Inbred SHR Rats; Infarction; Inflammation; Injury; Interneurons; Intervention; Investigation; Ischemia; Length; Link; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Microglia; Middle Cerebral Artery Occlusion; Modeling; Motor; Neurologic Dysfunctions; Neurons; Outcome; Oxygen; Pathway interactions; Peptide Hydrolases; Play; Positioning Attribute; Prevalence; Prevention; Process; Production; Proteins; Recovery; Recovery of Function; Regulation; Role; Sensory; Signal Transduction; Site; Source; Staging; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Time; Tissues; adult neurogenesis; cell motility; cell type; central nervous system injury; chemokine; chemokine receptor; cytokine; deprivation; effective therapy; immunoregulation; improved; in vivo; in vivo Model; inhibitor/antagonist; injured; macrophage; migration; nerve stem cell; neural initiation; neural recruitment; neuroblast; neurogenesis; neurological recovery; neuromechanism; neuron loss; neurotoxic; neurotrophic factor; newborn neuron; novel; novel therapeutics; prevent; receptor; relating to nervous system; repaired; response; response to injury; stem; subventricular zone

DESCRIPTION (provided by applicant): Stroke constitutes the third leading cause of death in the world and is the number one cause of sensory, motor and cognitive dysfunction in adults, with few effective therapies available. Recent studies have shown, however, that the adult CNS has an innate, albeit limited, ability to repair itself through the migration of endogenous neural stem/progenitor cells (NSPCs) from the subventricular zone (SVZ) to the site of injury, which have the capacity of forming mature neuronal cell types. However, this repair mechanism is not currently well understood, and is hindered by low survival of newly generated cells in the ischemic environment. Here, we investigate the role of resident and blood borne microglia/macrophages in initiating the neurogenic repair process by promoting migration of endogenous NSPCs to peri-infarct regions by release of a specific chemotactic cytokine, Stromal Derived Factor-1 alpha (SDF-1alpha). Our preliminary studies show that through secretion of SDF-1 alpha by microglial cells acutely, the innate immune response is critical in promoting the migration of NSPCs to peri-infarct sites, linking the immune response post-ischemia to the neural repair mechanisms that occur through the process of adult neurogenesis. Conversely, in the chronic stages post ischemia, our initial studies also show that SDF-1 can be proteolytically truncated into a neurotoxic form after ischemia, possibly by matrix metalloproteinase activity. These findings reveal a potential novel mechanism of NSPC cell death after ischemia that is induced by the truncation of SDF-1 due to factors within the injured neurovascular niche, and is consistent with the significant NSPC cell death hindering the endogenous neurogenic repair process. We propose, therefore, that the immune response coupled to the release of SDF-1 by microglia/macrophages can regulate both (1) the migration and differentiation of NSPCs through a SDF- 1/CXCR4 dependent pathway in the acute period post-ischemia, as well as (2) initiate NSPC cell death through truncated SDF-1 acting through a CXCR3 dependent pathway in the chronic phase, mediating cell death. These diverging roles of SDF-1 form a time-dependent axis of SDF-1 activity possibly regulated by the presence of MMP proteases in the ischemic neurovascular niche, and the indepth investigation of both MMP activity and SDF-1 alpha truncation will be critical in enhancing NSPC survival, a central theme for the current study. Careful regulation of this immune response and prevention of SDF- 1 alpha truncation post-ischemia through interventional strategies will be carried out in this study to assess novel therapies for neural stem cell survival and maturation of NSPCs into functional neurons that can improve neurological recovery post-ischemic insult.

描述（由申请人提供）：中风构成世界上第三大死亡原因，是成人感觉，运动和认知功能障碍的第一大原因，几乎没有有效的疗法。然而，最近的研究表明，成年中枢神经系统具有天生的（尽管有限），但能够通过内源性神经茎/祖细胞（NSPC）从亚室下区（SVZ）迁移到损伤部位，这些能力具有形成成熟神经元细胞类型的损伤部位。但是，目前尚不清楚这种修复机制，并且由于缺血性环境中新产生的细胞的存活较低而阻碍了这种修复机制。在这里，我们通过释放特定的趋化细胞因子，基质衍生因子-1 Alpha（SDF-1Alpha）来促进内源性NSPC迁移到侵袭周围区域，研究居民和血液传播的小胶质细胞/巨噬细胞在启动神经源修复过程中的作用。我们的初步研究表明，通过小胶质细胞对SDF-1α的分泌，敏锐的细胞对促进NSPC迁移到侵袭性部位的迁移至关重要，将免疫反应后缺血后的迁移与通过成人神经发生过程发生的神经修复机制联系起来。相反，在缺血后的慢性阶段中，我们的初步研究还表明，缺血后的SDF-1可以将蛋白水解截断为神经毒性形式，可能是基质金属蛋白酶活性。这些发现揭示了缺血后NSPC细胞死亡的潜在新机制，该机制是由于受伤的神经血管壁she中的因素引起的SDF-1引起的，并且与妨碍内源性神经源性修复过程的显着NSPC细胞死亡一致。 We propose, therefore, that the immune response coupled to the release of SDF-1 by microglia/macrophages can regulate both (1) the migration and differentiation of NSPCs through a SDF- 1/CXCR4 dependent pathway in the acute period post-ischemia, as well as (2) initiate NSPC cell death through truncated SDF-1 acting through a CXCR3 dependent pathway in the chronic phase,介导细胞死亡。 SDF-1的这些不同作用形成了可能受到缺血性神经血管构元中MMP蛋白酶存在可能调节的SDF-1活性的时间依赖性轴，并且MMP活性和SDF-1 AlphA截断的内在研究对于增强NSPC生存的NSPC生存是至关重要的。在本研究中将仔细调节这种免疫反应和预防SDF-1α截断后缺血后截断，以评估NSPC在功能神经元中的神经干细胞存活和成熟到功能性神经元中的新疗法，这些疗法可以改善神经学后恢复后的神经学恢复后疾病。