Transplantation of glial precursors: Astrocyte replacement in ALS
神经胶质前体移植:ALS 中的星形胶质细胞替代
基本信息
- 批准号:7394082
- 负责人:
- 金额:$ 5.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-03-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAffectAmyotrophic Lateral SclerosisAnimalsApoptoticAreaAstrocytesAxonBehavioralBody Weight decreasedBrainCell TransplantationCell TransplantsCellsCervicalCervical spinal cord structureCessation of lifeClinicalDiagnosisDiseaseDisease ProgressionEngineeringExperimental ModelsFunctional disorderGRP geneGenesGlutamate TransporterGlutamatesGray unit of radiation doseHornsImmuneIndividualInfiltrationInflammationLifeLimb structureMeasuresModelingMorphologyMotorMotor NeuronsMuscleMuscle FibersNatureNerve DegenerationNeuraxisNeurogliaNeuronsNumbersOligodendrogliaOutcomeParalysedPatientsPerformancePublic HealthRattusRespiratory DiaphragmRespiratory FailureRespiratory ParalysisRespiratory physiologyRodent ModelSpinal CordSpinal Cord DiseasesStagingStem cell transplantStructure of phrenic nerveSymptomsTestingTherapeuticThickTransplant RecipientsTransplantationTraumatic CNS injuryTreatment EfficacyUbiquitinVentral RootsWeightWorkastrogliosisbasecell typegray matterillness lengthin vivointerestmigrationnerve supplynervous system disorderneurofilamentneuron lossneuroprotectionprecursor cellrelating to nervous systemrespiratorytumoruptake
项目摘要
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), a motor neuron disorder that affects approximately 30,000 individuals in the U.S. alone, is characterized by relatively rapid degeneration of upper and lower motor neurons, with death normally occurring 2-5 years following diagnosis due to respiratory paralysis. Transplantation of neural precursor cells (NPCs) is a promising therapeutic strategy for treatment of traumatic CNS injury and neurodegeneration, including ALS, because of the ability to replace lost or dysfunctional CNS cell types, provide neuroprotection, and deliver gene factors of interest. Previous NPC transplantation studies in ALS therapy have focused mostly on motor neuron replacement; however, this is a challenging strategy because of problems associated with motor neuron differentiation and establishment of connections with host neurons and musculature. Studies in ALS models have suggested that cellular abnormalities are not limited to motor neurons. Given these observations, this proposal aims to target the replacement of non-neuronal cell types for possible therapeutic benefits. Specifically, the therapeutic potential of Glial-Restricted Precursors (GRPs) - lineage-restricted NPCs whose differentiation is restricted to astrocytes and oligodendrocytes - will be assessed following transplantation into the spinal cord of SOD1G93A rats, a rodent model of ALS. Wild-type GRPs or GRPs engineered to over-express the astroglial glutamate transporter, GL1T1, will be transplanted into the ventral horn of the cervical spinal cord of SOD1G93A rats. In Aim #1, fate of transplanted cells will be examined, including survival, migration, differentiation, and glutamate uptake. In Aim #2, transplant recipient animals will be assessed for a number of phenotypic and pathohistologic measures to determine therapeutic efficacy of transplanted cells. In Aim #3, the ability of transplanted GRPs to specifically rescue diaphragm function will be tested. Lay summary: Amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease) is a devastating nervous system disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of stem cells derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS because of their unique ability to replace lost or dysfunctional cell types. The work proposed in this study is of great therapeutic relevance to public health because it aims to utilize transplantation of stem cells to replace dysfunctional cells types that contribute to disease progression in ALS, potentially slowing or halting disease.
描述(由申请人提供):肌萎缩侧索硬化症 (ALS) 是一种运动神经元疾病,仅在美国就影响了约 30,000 人,其特点是上运动神经元和下运动神经元相对快速退化,通常在诊断后 2-5 年内因呼吸麻痹而死亡。神经前体细胞 (NPC) 移植是治疗创伤性 CNS 损伤和神经变性(包括 ALS)的一种有前途的治疗策略,因为它能够替代丢失或功能失调的 CNS 细胞类型,提供神经保护并传递感兴趣的基因因子。先前用于 ALS 治疗的 NPC 移植研究主要集中于运动神经元替代;然而,这是一个具有挑战性的策略,因为与运动神经元分化以及与宿主神经元和肌肉组织建立连接相关的问题。 ALS 模型的研究表明细胞异常不仅限于运动神经元。鉴于这些观察结果,该提案旨在以替代非神经元细胞类型为目标,以获得可能的治疗益处。具体来说,神经胶质限制性前体(GRP)——谱系限制性 NPC,其分化仅限于星形胶质细胞和少突胶质细胞——移植到 SOD1G93A 大鼠(一种 ALS 啮齿动物模型)的脊髓后,将评估其治疗潜力。野生型 GRP 或经过工程改造以过度表达星形胶质细胞谷氨酸转运蛋白 GL1T1 的 GRP 将被移植到 SOD1G93A 大鼠颈髓腹角。在目标#1中,将检查移植细胞的命运,包括存活、迁移、分化和谷氨酸摄取。在目标#2中,将评估移植受体动物的许多表型和病理组织学指标,以确定移植细胞的治疗效果。在目标 3 中,将测试移植的 GRP 特异性挽救膈肌功能的能力。概要:肌萎缩侧索硬化症(ALS 或卢伽雷氏病)是一种破坏性的神经系统疾病,会导致瘫痪并最终因呼吸衰竭而死亡。源自中枢神经系统的干细胞移植是治疗 ALS 等大脑和脊髓疾病的一种有前途的治疗策略,因为它们具有替代丢失或功能失调的细胞类型的独特能力。这项研究提出的工作对公共卫生具有重要的治疗意义,因为它的目的是利用干细胞移植来替代导致 ALS 疾病进展的功能障碍细胞类型,从而有可能减缓或阻止疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Angelo C Lepore其他文献
Angelo C Lepore的其他文献
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{{ truncateString('Angelo C Lepore', 18)}}的其他基金
Targeting chronic neuropathic pain after SCI using human iPS cell transplantation
利用人类 iPS 细胞移植治疗 SCI 后的慢性神经性疼痛
- 批准号:
9566583 - 财政年份:2017
- 资助金额:
$ 5.58万 - 项目类别:
Respiratory Motor Neuron Protection Following Cervical Spinal Cord Injury
颈脊髓损伤后呼吸运动神经元的保护
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9234425 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Respiratory Motor Neuron Protection Following Cervical Spinal Cord Injury
颈脊髓损伤后呼吸运动神经元的保护
- 批准号:
8623154 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Exploring mechanisms of axon growth and circuit connectivity for promoting respiratory function recovery following cervical spinal cord injury
探索轴突生长和回路连接促进颈脊髓损伤后呼吸功能恢复的机制
- 批准号:
10356158 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Respiratory interneuron circuit plasticity: promoting recovery of diaphragm function after spinal cord injury
呼吸中间神经元回路可塑性:促进脊髓损伤后膈肌功能的恢复
- 批准号:
10658185 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Respiratory Motor Neuron Protection Following Cervical Spinal Cord Injury
颈脊髓损伤后呼吸运动神经元的保护
- 批准号:
8503184 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Respiratory Motor Neuron Protection Following Cervical Spinal Cord Injury
颈脊髓损伤后呼吸运动神经元的保护
- 批准号:
9001833 - 财政年份:2013
- 资助金额:
$ 5.58万 - 项目类别:
Transplantation of glial precursors: Astrocyte replacement in ALS
神经胶质前体移植:ALS 中的星形胶质细胞替代
- 批准号:
7591052 - 财政年份:2008
- 资助金额:
$ 5.58万 - 项目类别:
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