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: 8494101
• 负责人: Chandler Walker
• 金额: $ 1.5万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494101
• 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脊髓损伤模型中是毁灭性的，会导致感觉运动缺陷，甚至可能导致完全瘫痪。不幸的是，没有有效的治疗方法，成千上万的人患有这种疾病，每年有成千上万的人被诊断出来。克服原发性损伤，以及继发性组织损伤和神经胶质瘢痕形成，对于促进脊髓损伤后轴突再生和功能恢复至关重要。细胞移植是一种很有潜力的治疗脊髓损伤的方法。雪旺细胞（SCs）是研究最广泛的细胞，这些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SC移植的全部潜力尚未被发现。挫伤损伤是最常见的脊髓损伤诊断形式之一，然而许多研究使用半或横断模型，临床价值较低。利用基因修饰的神经干细胞过度表达神经营养因子，有望成为脊髓损伤后的潜在治疗方法。我们最近在半解剖的脊髓损伤模型中表明，移植工程化的神经干细胞过度表达神经胶质细胞系来源的神经营养因子（SC-GDNF）可以增强脊髓损伤后的神经保护和修复，促进星形胶质细胞向移植部位迁移，减少神经胶质瘢痕成分的抑制性。此外，与单独使用SC移植相比，在挫伤性脊髓损伤后联合使用SC和GDNF可促进显著的神经保护和再生。然而，SC-GDNF移植对挫伤性脊髓损伤的短期和长期益处尚不清楚。此外，GDNF介导结构保护和修复，或非常重要的功能恢复的机制仍不清楚。激活PI3K-Akt通路中的促存活蛋白mTOR可能是GDNF发挥这种作用的一种潜在方式。此外，移植SCs表达GDNF对宿主组织和功能的长期影响尚不清楚。为了充分优化该疗法的临床应用潜力，有必要研究GDNF在挫伤性脊髓损伤亚慢性和慢性期对神经保护、功能恢复和轴突再生的作用，以及其促进损伤后神经再生的机制。根据这些目标，我们假设在胸挫伤脊髓病变中移植经过基因工程改造的过表达GDNF的SC将1)在亚慢性时间过程中增强神经保护、轴突保留/再生和功能恢复2)在脊髓损伤后的长期慢性阶段促进并增强这些益处3)通过激活mTOR作为其作用的一种新机制来增强神经突生长。