Genetic and physiological comparison of native human sensory neurons and induced pluripotent stem cells differentiated to sensory neurons
天然人类感觉神经元和分化为感觉神经元的诱导多能干细胞的遗传和生理比较
基本信息
- 批准号:10573702
- 负责人:
- 金额:$ 44.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-08 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAfferent NeuronsAnalgesicsAnatomyAnimal ModelAnimalsBenchmarkingBiological AssayBiopsyCalciumCatalogsCell NucleusCellsCellular MorphologyChronicClinicalComparative StudyComplementDataDiseaseDisease ProgressionDisease modelElectrophysiology (science)ExhibitsExposure toFemaleFibroblastsFutureGene ExpressionGene Expression ProfileGenerationsGeneticGenomicsGenotypeHeterogeneityHumanImageIn VitroIndividualInjuryInvestigationKnowledgeLibrariesMapsMedicalMembraneMethodologyModelingNatural regenerationNatureNerve RegenerationNeuronsNeuropathyNociceptionNociceptorsOrgan DonorOutputPaclitaxelPathologyPatientsPeripheral Nervous SystemPhysiologicalPhysiologyPopulationPositioning AttributeProcessQuantitative Reverse Transcriptase PCRRecoveryRegenerative MedicineResearchSamplingSensorySideSignal PathwaySignal TransductionSkinSourceSpinal GangliaTestingTherapeuticTimeTissue DonorsTissuesValidationbasecell typechemotherapychemotherapy induced neuropathyclinically relevantdifferentiation protocoldrug discoveryhuman stem cellshuman tissueimprovedinduced pluripotent stem cellinnovationmalemolecular subtypespatch clamppre-clinicalresponseresponse to injurystem cell differentiationstem cellssuccesstherapeutic developmenttherapeutic evaluationtooltranscriptome sequencingtranslation to humanstranslational potential
项目摘要
Project Summary
Sensory neurons in the dorsal root ganglia are the primary source of nociceptive (pain) signaling and are
susceptible to genetic and functional alterations as a result of injury or disease, thus resulting in chronic pain.
Understanding the mechanisms underlying these alterations and gaining the capability to reverse them is a
major objective of pain research, and is expected to produce medical advances that reduce patient suffering.
Most of the existing information on these neurons is derived from animal models, which has unfortunately led
to few clinical successes. Recently, increased access and use of human dorsal root ganglia as well as sensory
neurons derived from human induced pluripotent stem cells have positioned the field to improve mechanistic
understanding in human cells and advance translation to human drug discovery. However, research on native
human sensory neurons and differentiated sensory neurons from human stem cells have progressed on
independent trajectories, and therefore have not been adequately compared, leaving open the likely possibility
that differentiated stem cells exhibit differences from native sensory neurons that are critical for understanding
injury and disease progression toward chronic pain. This application aims to first produce a map of gene
expression comparing native and stem cell-derived sensory neurons from the same donors. The results will
show precisely how well stem cell-derived sensory neurons genetically match to their native human sensory
neurons counterparts, and therefore these data can be utilized to guide differentiation protocols and improve
the validity and interpretability of stem cell-derived sensory neurons. Second, native human sensory neurons
and sensory neurons derived from stem cells will be assessed for key functional alterations evoked by
chemotherapy-induced neuropathy, a common clinical cause of chronic pain. Here, a functional signaling
pathway leading to chronic pain will be sampled in each population of cells to expand knowledge of human
neuropathy and determine whether sensory neurons derived from stem cells offer a valid model of neuropathy.
This project will uncover the nature of both native and differentiated sensory neurons and significantly advance
both models as tools for therapeutic development in chronic pain, neuropathy, and regeneration of the
peripheral nervous system.
项目摘要
背根神经节中的感觉神经元是伤害性(疼痛)信号传导的主要来源,
易受损伤或疾病导致的遗传和功能改变的影响,从而导致慢性疼痛。
理解这些改变的机制并获得逆转它们的能力是一个
这是疼痛研究的主要目标,并有望产生减少患者痛苦的医学进步。
大多数关于这些神经元的现有信息都来自动物模型,不幸的是,
临床上的成功案例很少。最近,越来越多的人背根神经节以及感觉神经节的进入和使用,
从人类诱导多能干细胞衍生的神经元已经定位于改善机制的领域。
了解人类细胞和先进的翻译人类药物的发现。然而,对原住民的研究
人类感觉神经元和来自人类干细胞的分化的感觉神经元已经在
独立的轨迹,因此没有进行充分的比较,留下了可能的可能性
分化的干细胞表现出与天然感觉神经元的差异,
损伤和疾病进展为慢性疼痛。这个应用程序的目的是首先产生一个基因图谱
比较来自相同供体的天然和干细胞衍生的感觉神经元的表达。结果将
精确地显示了干细胞衍生的感觉神经元在遗传上与其天然人类感觉神经元的匹配程度。
神经元对应物,并且因此这些数据可以用于指导分化方案并改善
干细胞来源的感觉神经元的有效性和可解释性。第二,人类的感觉神经元
来自干细胞的感觉神经元将被评估由以下引起的关键功能改变:
化疗引起的神经病变,慢性疼痛的常见临床原因。这里,一个功能性信号
将在每个细胞群中对导致慢性疼痛的通路进行采样,以扩大对人类疼痛的认识。
神经病变,并确定是否感觉神经元来源于干细胞提供了有效的神经病变模型。
该项目将揭示天然和分化的感觉神经元的性质,并显着推进
这两种模型都是慢性疼痛、神经病变和神经再生的治疗开发工具。
外周神经系统
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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Steve Davidson其他文献
Steve Davidson的其他文献
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{{ truncateString('Steve Davidson', 18)}}的其他基金
Functional Characterization and Sensitization of Human Pruriceptors
人类瘙痒感受器的功能特征和敏感性
- 批准号:
9035997 - 财政年份:2016
- 资助金额:
$ 44.55万 - 项目类别:
Reversal of pain by group II metabotropic glutamate receptors
II 类代谢型谷氨酸受体逆转疼痛
- 批准号:
8366988 - 财政年份:2011
- 资助金额:
$ 44.55万 - 项目类别:
Reversal of pain by group II metabotropic glutamate receptors
II 类代谢型谷氨酸受体逆转疼痛
- 批准号:
8255236 - 财政年份:2011
- 资助金额:
$ 44.55万 - 项目类别:
Central Nerual Mechanisms Involved in the Control of Itch
参与控制瘙痒的中枢神经机制
- 批准号:
7388995 - 财政年份:2007
- 资助金额:
$ 44.55万 - 项目类别:
Central Nerual Mechanisms Involved in the Control of Itch
参与控制瘙痒的中枢神经机制
- 批准号:
7576850 - 财政年份:2007
- 资助金额:
$ 44.55万 - 项目类别:
Central Nerual Mechanisms Involved in the Control of Itch
参与控制瘙痒的中枢神经机制
- 批准号:
7275086 - 财政年份:2007
- 资助金额:
$ 44.55万 - 项目类别:
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