Grafting genetically-modified Schwann cells into a clinically-relevant SCI model

将转基因雪旺细胞移植到临床相关 SCI 模型中

• 批准号: 8061914
• 负责人: Chandler Walker
• 金额: $ 3.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2014-02-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061914
• 关键词: Acute; Address; Affect; Brain; Cell Survival; Cell Transplantation; Cells; Chest; Chronic; Cicatrix; Clinical; Diagnosis; Disease; Exhibits; Foundations; GDNF gene; Goals; Growth; In Vitro; Individual; Injury; Ischemia; Life; Link; Long-Term Effects; Mediating; Modeling; Molecular; Motor; Natural regeneration; Nervous system structure; Neurites; Neurons; Paralysed; Pathway interactions; Property; Proteins; Recovery; Recovery of Function; Regulation; Research; Schwann Cells; Secondary to; Signal Transduction; Site; Spinal; Spinal Cord Lesions; Spinal cord injury; Staging; Time; Tissues; Transplantation; axon regeneration; cancer therapy; cellular engineering; clinically relevant; design; disability; effective therapy; experience; genetically modified cells; glial cell-line derived neurotrophic factor; improved functioning; in vivo; injured; insight; mTOR protein; migration; myelination; neuroprotection; neurotrophic factor; novel; overexpression; regenerative; relating to nervous system; repaired; treatment strategy

DESCRIPTION (provided by applicant): Grafting genetically-modified Schwann cells into a clinically-relevant model of SCI Spinal cord injury (SCI) is devastating, causing sensorimotor deficiencies, and possibly, complete paralysis. Unfortunately, there is no effective treatment, with hundreds of thousands living with the disorder and thousands more diagnosed each year. Overcoming primary damage, in addition to secondary tissue injury and glial scar formation, is critical for promoting axonal regeneration and functional recovery following SCI. Cell transplantation is a promising potential treatment for SCI. Schwann cells (SCs) are the most widely studied and these cells exhibit many benefits following SCI, such as promoting axonal regeneration and enhancing myelination. Though these functions are certainly advancements in SCI treatment, the full potential of SC transplantation has yet to be uncovered. Contusive injuries are one of the most commonly diagnosed forms of SCI, however much research has utilized hemi- or transection models, which are of less clinical value. Using SCs genetically modified to overexpress neurotrophic factors is promising as a potential treatment following SCI. We have recently shown that transplanting SCs engineered to overexpress glial cell line-derived neurotrophic factor (SC-GDNF) enhances neuroprotection and repair following SCI, and promotes astrocytic migration into the graft site, reducing inhibitory glial scar components in a hemisection SCI model. Also, co- administering SCs with GDNF following contusive SCI promotes significant neuroprotection and regeneration compared to SC transplantation alone. However, it is still not known what the short and long-term benefits of SC-GDNF transplantation are in contusive spinal cord injury. Also, the mechanism by which GDNF mediates structural protection and repair, or, very importantly, recovery of function, remains unknown. Activating mTOR, a pro-survival protein in the PI3K-Akt pathway may be one potential way GDNF exerts such effects. In addition, the long-term effects of GDNF expression by transplanted SCs on host tissue and function is unclear. To fully optimize this therapy for potential clinical use, it is essential to characterize the GDNF effect on neuroprotection, functional recovery and axonal regeneration in sub-chronic and chronic stages following contusive SCI, as well as its mechanism in enhancing neural regrowth following injury . In line with these goals, we hypothesize that transplanting SC engineered to overexpress GDNF into a thoracic contusive spinal cord lesion will 1) enhance neuroprotection, axonal sparing/regeneration, and functional recovery within a sub- chronic time course 2) promote and enhance such benefits into long-term chronic stages following SCI 3) enhance neurite outgrowth via activation of mTOR as a novel mechanism of its action. PUBLIC HEALTH RELEVANCE: Spinal cord injury affects over 200,000 individuals, with over 10,000 new cases per year. There is currently no effective treatment, though cell transplantation is a promising option. This study plans to investigate the effects of transplanting genetically-modified cells, Schwann cells, for repairing and protecting injured tissue and improving function following spinal cord injury.

描述(申请人提供)：将转基因雪旺细胞移植到临床相关的脊髓损伤(SCI)模型中是毁灭性的，会导致感觉运动障碍，甚至可能完全瘫痪。不幸的是，没有有效的治疗方法，每年有数十万人患有这种疾病，另有数千人被诊断出患有这种疾病。克服原发损伤，继发性组织损伤和胶质瘢痕形成，对于促进脊髓损伤后轴突再生和功能恢复至关重要。细胞移植是治疗脊髓损伤的一种很有前途的治疗方法。雪旺细胞(Schwann cell，SCs)是研究最广泛的细胞，在脊髓损伤后表现出许多益处，如促进轴突再生和增强髓鞘形成。虽然这些功能无疑是脊髓损伤治疗的进步，但干细胞移植的全部潜力尚未被发现。结论损伤是脊髓损伤最常见的诊断形式之一，然而许多研究使用了半横断模型，这些模型的临床价值较低。使用转基因的干细胞过表达神经营养因子有望成为脊髓损伤后的一种潜在的治疗方法。我们最近发现，移植高表达胶质细胞源性神经营养因子(SC-GDNF)的干细胞可以增强脊髓损伤后的神经保护和修复，并促进星形胶质细胞迁移到移植物部位，减少半切脊髓损伤模型中抑制胶质瘢痕的成分。此外，与单独应用干细胞移植相比，在挫伤脊髓损伤后联合应用干细胞和GDNF可显著促进神经保护和再生。然而，目前尚不清楚SC-GDNF移植在挫伤脊髓损伤中的近期和远期疗效。此外，GDNF介导结构保护和修复，或者更重要的是，功能恢复的机制仍不清楚。激活PI3K-Akt通路中的一种促生存蛋白mTOR可能是GDNF发挥这种作用的一种潜在方式。此外，移植的干细胞表达GDNF对宿主组织和功能的长期影响尚不清楚。为了充分优化这一治疗方法，使其具有潜在的临床应用价值，有必要明确GDNF在亚慢性和慢性脊髓挫伤后的神经保护、功能恢复和轴突再生中的作用，以及其促进损伤后神经再生的机制。根据这些目标，我们假设将高表达GDNF的干细胞移植到胸部挫伤脊髓损伤中将1)在亚慢性时间过程中增强神经保护、轴突保护/再生和功能恢复2)促进和增强这些益处进入脊髓损伤后的长期慢性阶段3)通过激活mTOR作为其新的作用机制促进轴突生长。 公共卫生相关性：脊髓损伤影响到20多万人，每年新增病例超过10,000例。目前还没有有效的治疗方法，尽管细胞移植是一个有希望的选择。本研究旨在探讨移植转基因雪旺细胞对脊髓损伤后损伤组织的修复和保护作用，以及对脊髓损伤后功能的改善作用。