Targeting chronic neuropathic pain after SCI using human iPS cell transplantation
Targeting chronic neuropathic pain after SCI using human iPS cell transplantation
批准号:
9566583
负责人:
Angelo C Lepore
金额:
$41.87万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-25 至 2019-08-31
关键词:
AddressAffectAffectiveAlpha CellAnimal ModelAstrocytesAttenuatedAutologousBehaviorCell CommunicationCell TransplantationCellsCentral Nervous System DiseasesCervicalCervical spinal cord injuryCervical spinal cord structureChronicClinicalConflict (Psychology)ContusionsDataDerivation procedureDiseaseEngineeringEtiologyFunctional disorderGlutamate TransporterGlutamatesGoalsHomeostasisHumanInflammatoryInjuryMechanicsMediatingMethodsMicrogliaModelingMotivationMusNatureNeurogliaNeuronsNociceptionOutcomePainPatientsPeripheralPhenotypePlayPosterior Horn CellsPreparationQuality of lifeRattusRegulationRodent ModelRoleSourceSpinal CordSpinal Cord ContusionsSpinal cord injurySpinal cord injury patientsStem cell transplantSynaptic TransmissionTactileTestingTherapeuticThermal HyperalgesiasTimeTissuesTransplantationTreatment Efficacyallodyniabasecell typechronic neuropathic painchronic painclinically relevantdorsal horneffective therapyextracellularfunctional outcomesimmunohistochemical markersimprovedinduced pluripotent stem cellmacrophagemonocyteneurotransmissionnovelnovel strategiesoverexpressionpainful neuropathypatch clamppatient populationpreventpsychologicresponsesensory inputstemtransmission processuptake
中文摘要
项目摘要/摘要
英文摘要
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.
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科研奖励(0)
会议论文
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批准号:9234425
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负责人:Angelo C Lepore
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依托单位:
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资助金额:$35.28万
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依托单位:
Transplantation of glial precursors: Astrocyte replacement in ALS
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批准号:7394082
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项目类别:
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资助金额:$5.58万
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财政年份:2008
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负责人:Angelo C Lepore
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依托单位:
Transplantation of glial precursors: Astrocyte replacement in ALS
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批准号:7591052
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资助金额:$5.78万
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负责人:Angelo C Lepore
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依托单位:
海外基金