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

基本信息

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
项目类别：
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

项目摘要

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）：将遗传改性的Schwann细胞嫁接到与临床上相关的SCI脊髓损伤模型（SCI）中是毁灭性的，导致感觉运动缺陷，可能是完全麻痹。不幸的是，没有有效的治疗方法，成千上万的患有这种疾病，每年诊断出数千个。除了次要组织损伤和胶质疤痕形成外，克服一级损害对于促进SCI后促进轴突再生和功能恢复至关重要。细胞移植是SCI的有希望的潜在治疗方法。 Schwann细胞（SC）是研究最广泛的，这些细胞在SCI后表现出许多好处，例如促进轴突再生和增强髓鞘形成。尽管这些功能无疑是SCI治疗方面的进步，但SC移植的全部潜力尚未发现。欺骗性伤害是最常见的SCI形式之一，但是很多研究都利用了临床价值较小的半部分或横切模型。使用遗传改性的SCS来表达过表达神经营养因素，这是SCI后的潜在治疗方法。我们最近表明，用于过表达神经胶质细胞系衍生的神经营养因子（SC-GDNF）的移植SCS可增强SCI后神经保护和修复，并促进星形胶质细胞迁移到移植物中，从而减少半径SCI模型中的抑制性神经胶质疤痕成分。同样，与单独的SC移植相比，与SCI相比，与SCI相比，与GDNF共同管理SC会促进明显的神经保护和再生。但是，仍然不知道SC-GDNF移植的短期和长期益处在脊髓损伤中是什么。同样，GDNF介导结构保护和修复的机制，或者非常重要的是，功能的恢复仍然未知。激活MTOR，PI3K-AKT途径中的促生存蛋白可能是GDNF发挥这种影响的一种潜在方式。此外，移植后的SC表达GDNF对宿主组织和功能的长期影响尚不清楚。为了充分优化这种潜在临床用途的治疗，必须表征GDNF对康复SCI后亚尚体和慢性阶段的神经保护作用，功能恢复和轴突再生的影响，以及其在受伤后增强神经再生的机制。与这些目标一致，我们假设移植SC工程为过表达GDNF中的胸腔污染性脊髓病变将1）增强神经保护性，轴突隔离/再生/再生，并在子长期时间过程中增强和增强此类益处的效果，并增强了sci的长期阶段，以促进和增强sci的长期阶段。行动。