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

基本信息

  • 批准号:
    9566583
  • 负责人:
  • 金额:
    $ 41.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-25 至 2019-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary / Abstract Stem/progenitor cell transplantation-based replacement of astrocytes is a novel and potentially powerful therapeutic strategy for treating CNS diseases such as traumatic spinal cord injury (SCI). Towards this goal, we propose to test transplantation of human induced Pluripotent Stem (iPS) cell-derived astrocytes (hiPSAs) for mitigating SCI-induced neuropathic pain. A major portion of SCI patients suffer from neuropathic pain, resulting in often long-term physical and psychological burdens. Effective treatments for this debilitating outcome of SCI are currently lacking; therefore, novel and robust therapeutic approaches are urgently needed. Following SCI, chronic dysregulation of extracellular glutamate homeostasis plays a key role in persistent central hyperexcitability of superficial dorsal horn (DH) neurons that mediate pain neurotransmission, leading to neuropathic pain. Astrocytes are the principal cell type that expresses the glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in the intact CNS, particularly in spinal cord. In our rodent model of cervical contusion SCI that results in persistent neuropathic pain, we find significant and long-lasting reductions in GLT1 expression and functional GLT1-mediated glutamate uptake in cervical DH. iPS cells are a novel and clinically-relevant source for homogeneous derivation of mature cell types in large quantities for applications such as transplantation, potentially in an autologous fashion from the eventual patient recipient. The use of iPS cell transplantation to deliver astrocytes represents an exciting strategy that has not been extensively studied to date, particularly with respect both to targeting key astrocyte functions such as glutamate uptake at a mechanistic level and to addressing neuropathic pain. Importantly, a majority of human spinal cord trauma cases affect cervical regions and are of the contusion/compression type, urgently calling for the assessment of disease etiology and treatment of neuropathic pain specifically in models of cervical contusion SCI to provide relevance to the patient population. In Aim 1a, we will determine whether hiPSA transplantation can reverse several forms of established neuropathic pain-related behavior in a rat model of cervical contusion. Importantly, we will assess motivational and affective components of pain using an operant paradigm. In Aim 1b, we will determine whether hiPSAs can reduce hyperexcitability of DH pain neurons using whole-cell patch clamp recording in an intact ex vivo preparation. In Aim 2a, we will examine the ability of hiPSA transplants to express GLT1 and to restore GLT1- mediated glutamate uptake levels in DH after cervical contusion. We will also engineer hiPSAs to overexpress GLT1 to enhance their therapeutic potential. In Aim 2b, we will examine whether hiPSAs can alter the DH microglia/macrophage response that plays a central role in hyperexcitability and chronic pain. We will assess whether hiPSAs can shift this response after SCI away from a M1 pro-inflammatory phenotype (and toward a M2 reparative phenotype) as an additional - and potentially powerful - mechanism of hiPSA transplant action.
项目摘要/摘要

项目成果

期刊论文数量(0)
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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

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:
    9234425
  • 财政年份:
    2013
  • 资助金额:
    $ 41.87万
  • 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:
    $ 41.87万
  • 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:
    $ 41.87万
  • 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:
    $ 41.87万
  • 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:
    $ 41.87万
  • 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:
    $ 41.87万
  • 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:
    7394082
  • 财政年份:
    2008
  • 资助金额:
    $ 41.87万
  • 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:
    $ 41.87万
  • 项目类别:

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