Neuronal and Astrocytic Interaction in Recovery after Stroke

中风后恢复中神经元和星形胶质细胞的相互作用

• 批准号: 9973176
• 负责人: Jun Li
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973176
• 关键词: Adult; Aging; Astrocytes; Axon; Brain; Brain Injuries; Cells; Chondroitin Sulfate Proteoglycan; Cicatrix; Coculture Techniques; Critical Care; Data; Diffusion Magnetic Resonance Imaging; Emergency Care; Environment; Genes; Glial Fibrillary Acidic Protein; Glucose; Goals; Growth; Growth Cones; In Vitro; Injury; Investigation; Ischemia; Knockout Mice; Lentivirus Vector; Magnetic Resonance Spectroscopy; Modeling; Mus; Natural regeneration; Neuraxis; Neurites; Neurons; Outcome; Oxygen; Pathway interactions; Patients; Pharmacology; Play; Population; Process; Property; Proteins; Recovery; Recovery of Function; Regenerative response; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Stroke; System; Tamoxifen; Testing; Viral; age related; aged; aging brain; axon regeneration; cell type; cellular pathology; density; deprivation; disability; effective therapy; functional loss; improved; in vivo; inhibitor/antagonist; knock-down; neuronal growth; novel; overexpression; post stroke; pre-clinical; rac1 GTP-Binding Protein; regenerative; relating to nervous system; repaired; rho GTP-Binding Proteins; stroke patient; stroke survivor; stroke therapy; tool

Project Description Stroke is the primary cause of long-term disability. However, no effective treatment is available for the majority of stroke patients. Interestingly, a process of self-repair and recovery starts to occur days following stroke. Mounting evidence suggests that axonal plasticity is a critical aspect of this process, as it is essential for establishing new neural connections to compensate for the stroke-induced functional loss. However, after injury, this regrowth and remodeling in the adult mammalian central nervous system (CNS) is limited. The weak intrinsic growth capacity in neurons and the inhibitory factors from extrinsic glial environments are among the major causes that limit regeneration. This potential for regrowth has emerged as an alternative and potentially more tractable target in stroke research. Indeed, emerging data suggest that Ras-related C3 botulinum toxin substrate 1 (Rac1), a Rho GTPase, plays a central role in axonal regeneration in the injured brain, specifically by stimulating neuronal intrinsic growth and counteracting the growth inhibitory signaling that leads to growth cone collapse. The overall goal of this proposal is to define the functional role of Rac1 in neurite regeneration after stroke and uncover its underlying neuronal and astrocytic specific mechanisms. We showed that pharmacological inhibition of Rac1, starting one week after stroke, results in decreased functional recovery as well as reduced axonal density while post-stroke over-expression of Rac1 improves brain functional recovery. Furthermore, Rac1 inhibition decreases activation of intrinsic pro-regenerative molecules in mice after stroke and reduced axonal density in neuronal culture following oxygen-glucose deprivation. In contrast, inhibition of Rac1 increases glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycan (CSPG), both of which are major astrocytic inhibitory signals after ischemia. Finally, aging leads to a decline in the levels/activities of proteins involved in the Rac1 pathway in the brain, and we aim to test if activating this pathway in young and aging brains could enhance neurite regeneration and improve post-stroke functional recovery. We will use a combination of pharmacological tools, diffusion tensor imaging, inducible knockout mice and viral transduction systems to over-expression Rac1 in vivo. These studies represent the first steps in understanding the endogenous pathways that promote brain axonal regeneration and subsequently recovery following stroke.

项目说明 中风是导致长期残疾的主要原因。然而，大多数人还没有有效的治疗方法。 中风患者的比例。有趣的是，中风后几天就开始了自我修复和恢复的过程。 越来越多的证据表明，轴突可塑性是这一过程的关键方面，因为它是 建立新的神经连接以补偿中风引起的功能丧失。然而，在 损伤后，成年哺乳动物中枢神经系统(CNS)的这种再生和重塑是有限的。这个 神经元内源性生长能力弱和外源性神经胶质环境的抑制因子是其中之一。 限制再生的主要原因。这种重新生长的潜力已经成为一种替代方案 可能是中风研究中更容易处理的目标。事实上，新出现的数据表明，与RAS相关的C3 肉毒杆菌毒素底物1(Rac1)是一种Rho GTP酶，在损伤的轴突再生中起核心作用。 大脑，特别是通过刺激神经元的内在生长和对抗生长抑制信号 导致生长锥体坍塌。该提案的总体目标是定义rac1在 中风后轴突再生，并揭示其潜在的神经元和星形胶质细胞的特定机制。我们 结果表明，从中风后一周开始，药物抑制rac1会导致功能减退 卒中后rac1过度表达改善脑功能的恢复及轴突密度降低 功能恢复。此外，Rac1的抑制减少了内在的促再生分子的激活 在小鼠中风后和缺氧-葡萄糖剥夺后神经元培养中轴突密度降低。在……里面 相反，抑制rac1会增加胶质纤维酸性蛋白(GFAP)和硫酸软骨素蛋白多糖 (CSPG)，两者都是脑缺血后主要的星形胶质细胞抑制信号。最后，衰老会导致年龄的下降 大脑中参与rac1通路的蛋白质的水平/活性，我们的目标是测试是否激活了这一通路 年轻和老年大脑中的通路可以促进轴突再生和改善中风后的功能 恢复。我们将结合使用药理学工具，扩散张量成像，诱导基因敲除 小鼠和病毒转导系统在体内过表达rac1。这些研究代表着 了解促进脑轴突再生和随后恢复的内源性途径 中风后。

项目成果

Activation of neuronal Ras-related C3 botulinum toxin substrate 1 (Rac1) improves post-stroke recovery and axonal plasticity in mice.

• DOI: 10.1111/jnc.15195
• 发表时间: 2021-05
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Bu F;Munshi Y;Furr JW;Min JW;Qi L;Patrizz A;Spahr ZR;Urayama A;Kofler JK;McCullough LD;Li J
• 通讯作者: Li J

Activation of cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 promotes post-ischemic stroke functional recovery in aged mice.

• DOI: 10.4103/1673-5374.382256
• 发表时间: 2024-04
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Bu F;Min JW;Razzaque MA;El Hamamy A;Patrizz A;Qi L;Urayama A;Li J
• 通讯作者: Li J