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: 8470066
• 负责人: Chandler Walker
• 金额: $ 3.09万
• 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/8470066
• 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.

描述（由申请人提供）：将基因修饰的雪旺细胞移植到临床相关的SCI模型中脊髓损伤（SCI）是毁灭性的，导致感觉运动缺陷，并可能导致完全瘫痪。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，还有数千人被诊断出患有这种疾病。除了继发性组织损伤和胶质瘢痕形成之外，克服原发性损伤对于促进SCI后轴突再生和功能恢复至关重要。细胞移植是一种很有前途的脊髓损伤治疗方法。雪旺细胞（SC）是研究最广泛的，这些细胞在SCI后表现出许多益处，例如促进轴突再生和增强髓鞘形成。虽然这些功能在SCI治疗中肯定是进步的，但SC移植的全部潜力尚未被发现。挫伤是SCI最常见的诊断形式之一，然而，许多研究使用了半或横断模型，这些模型的临床价值较低。使用遗传修饰过表达神经营养因子的SC作为SCI后的潜在治疗是有希望的。我们最近的研究表明，移植过表达胶质细胞源性神经营养因子（SC-GDNF）的SC增强了SCI后的神经保护和修复，并促进星形胶质细胞迁移到移植部位，减少半切SCI模型中抑制性胶质瘢痕成分。此外，与单独的SC移植相比，在挫伤性SCI后共同施用SC与GDNF促进了显著的神经保护和再生。然而，目前尚不清楚SC-GDNF移植在挫伤性脊髓损伤中的短期和长期益处。此外，GDNF介导结构保护和修复的机制，或者非常重要的是，功能恢复的机制仍然未知。激活mTOR，PI 3 K-Akt通路中的促存活蛋白可能是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。为了充分优化这种治疗方法的潜在临床应用，有必要表征GDNF在挫伤性SCI后亚慢性和慢性阶段的神经保护、功能恢复和轴突再生的作用，以及其在损伤后促进神经再生的机制。与这些目标一致，我们假设将工程化以过表达GDNF的SC移植到胸挫伤性脊髓损伤中将1）在亚慢性时程内增强神经保护、轴突保留/再生和功能恢复，2）促进和增强SCI后长期慢性阶段的这种益处，3）通过激活mTOR作为其作用的新机制来增强神经突生长。