Investigating the role of CD44 and immune-neuro signaling mechanisms in neural stem cell responses after spinal cord injury
研究 CD44 和免疫神经信号传导机制在脊髓损伤后神经干细胞反应中的作用
基本信息
- 批准号:10467915
- 负责人:
- 金额:$ 45.03万
- 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:2022-06-21 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAntibodiesArchitectureAutomobile DrivingBloodCD44 geneCell LineCell NucleusCell TransplantationCellsCellular MorphologyChIP-seqChromatinChronicCicatrixComplement 1qComplexCytometryDataDemyelinationsDependenceDetectionEmbryoEngraftmentEpigenetic ProcessGene ActivationGene ExpressionGenesGenetic TranscriptionGoalsHematopoieticHeterochromatinHumanHyaluronic AcidImageImmuneImmune responseIn VitroInflammatoryInflammatory ResponseInjuryKnock-outKnockout MiceKnowledgeLesionLigandsLinkLocomotor RecoveryMMP9 geneMediator of activation proteinMedicalMesenchymalMethodsMicrogliaModificationMultiple SclerosisMusNatural regenerationPlayProteinsPublishingResolutionRodentRoleSerum ProteinsSignal InductionSignal TransductionSpinal CordSpinal cord injuryStem cell transplantTestingTherapeuticTissue PreservationTissuesTransmembrane DomainTransplantationWorkcell behaviorcofactorfunctional disabilitygamma secretasegene repressionin vivoin vivo Modelinjury and repairinsightmacrophagemigrationnerve stem cellnovelosteopontinprogenitorpromoterreceptorreceptor-mediated signalingrelating to nervous systemremyelinationrepairedresponsespatiotemporalstemstem cell fatestem cell genesstem cell migrationstem cellstranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Spinal cord injury (SCI) results in long-term functional impairments due to loss of cord tissue and limited
regeneration. Human neural stem cell (hNSC) transplantation has exciting potential as a treatment for
SCI, but the complex interactions between hNSC and the extrinsic microenvironment are poorly
understood. The objective of this proposal is to address this gap in knowledge, enabling both optimization
of therapeutic donor hNSC transplantation, as well as new insights into in vivo signaling/transcriptional
networks, and the consequence of these networks for hNSC localization and fate after SCI. Critical to this
is goal is elucidating mechanisms of immune-NSC signaling.
Spinal Cord Injury (SCI) causes disruption of the blood-spinal-cord barrier, and a robust influx of serum
proteins, including C1q. SCI also results in a multiphasic and prolonged immune response, in which
infiltrating and resident immune cells also secrete C1q. We have shown that C1q influx is chemoattractive
for transplanted hNSC, inducing hNSC migration towards and clustering at the injury epicenter, and driving
hNSC towards an astroglial lineage. Blockade of C1q in vivo releases both migration and lineage selection,
and enhances SCI repair and locomotor recovery. We have also shown that C1q directly modulates hNSC
migration, proliferation, and differentiation in vitro via a receptor-mediated signaling mechanism. Using an
unbiased screen, we identified novel interactions between C1q and five candidate receptors expressed by
hNSC. Among these is CD44, a receptor with an established role in regulating cellular behavior. Our
published data identify CD44 as a principal mediator of hNSC chemoattraction to C1q in vitro and in vivo,
and show that C1q-CD44 signaling also modulates hNSC fate. Further, CD44 deletion in hNSC in an acute
transplantation paradigm in vivo enhances SCI repair and locomotor recovery.
The central hypotheses of the proposed aims are that C1q-CD44 signaling in NSC alters the NSC
transcriptome via CD44-ICD heterochromatin modulation, and that deletion of CD44 in transplanted hNSC
after SCI will enhance repair. Aim 1 investigates the effect of CD44 KO on hNSC gene expression at
baseline and in response to the CD44 ligands C1q, HA, and osteopontin. Aim 2 tests the effect of CD44
deletion on the repair capacity of hNSC transplanted into the SCI microenvironment, and the dependence
of this effect on C1q. Aim 3 investigates the effect of CD44 KO in hNSC on localization and fate in relation
to signaling and transcriptional networks in vivo after SCI
项目摘要
脊髓损伤(SCI)由于脊髓组织的损失和有限的功能障碍,
再生人神经干细胞(hNSC)移植作为治疗神经系统疾病的一种方法具有令人兴奋的潜力。
SCI,但hNSC和外部微环境之间的复杂相互作用很差
明白本提案的目的是解决这一知识差距,
治疗性供体hNSC移植,以及体内信号传导/转录的新见解
网络,以及这些网络对SCI后hNSC定位和命运的后果。对此至关重要
目的是阐明免疫-NSC信号传导的机制。
脊髓损伤(SCI)导致血脊髓屏障的破坏和血清的大量涌入
蛋白质,包括C1 q。SCI还导致多相和延长的免疫反应,其中
浸润和驻留免疫细胞也分泌C1 q。我们已经证明C1 q内流是化学吸引的,
对于移植的hNSC,诱导hNSC向损伤中心迁移并聚集,
hNSC朝向星形胶质细胞谱系。体内C1 q的阻断释放了迁移和谱系选择,
并增强SCI修复和运动恢复。我们还表明,C1 q直接调节hNSC
通过受体介导的信号传导机制在体外迁移、增殖和分化。使用
通过无偏筛选,我们确定了C1 q和五种候选受体之间的新型相互作用,
hNSC。其中之一是CD 44,一种在调节细胞行为中具有既定作用的受体。我们
公开的数据鉴定了CD 44是体外和体内hNSC对C1 q化学吸引的主要介质,
并且显示C1 q-CD 44信号传导也调节hNSC命运。此外,急性脑梗死患者hNSC中的CD 44缺失
体内移植范例增强SCI修复和运动恢复。
提出的目标的中心假设是NSC中的C1 q-CD 44信号传导改变了NSC
通过CD 44-ICD异染色质调节转录组和移植的hNSC中的CD 44缺失
脊髓损伤后会加强修复。目的1研究CD 44 KO对hNSC基因表达的影响,
基线和对CD 44配体C1 q、HA和骨桥蛋白的应答。目的2检测CD 44的作用
缺失对移植到SCI微环境中的hNSC的修复能力的影响,
这对C1 q的影响。目的3研究CD 44 KO在hNSC中的定位和命运的影响,
脊髓损伤后体内的信号和转录网络
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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Aileen J Anderson其他文献
Aileen J Anderson的其他文献
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{{ truncateString('Aileen J Anderson', 18)}}的其他基金
Investigating the role of CD44 and immune-neuro signaling mechanisms in neural stem cell responses after spinal cord injury
研究 CD44 和免疫神经信号传导机制在脊髓损伤后神经干细胞反应中的作用
- 批准号:
10650327 - 财政年份:2022
- 资助金额:
$ 45.03万 - 项目类别:
Multi-channeled Bridges for Promoting Chronic Spinal Cord Repair
促进慢性脊髓修复的多通道桥
- 批准号:
10249977 - 财政年份:2020
- 资助金额:
$ 45.03万 - 项目类别:
Multi-channeled Bridges for Promoting Chronic Spinal Cord Repair
促进慢性脊髓修复的多通道桥
- 批准号:
10469553 - 财政年份:2020
- 资助金额:
$ 45.03万 - 项目类别:
Multi-channeled Bridges for Promoting Chronic Spinal Cord Repair
促进慢性脊髓修复的多通道桥
- 批准号:
10700124 - 财政年份:2020
- 资助金额:
$ 45.03万 - 项目类别:
Nanoparticle-mediated reprogramming of circulating monocytes and neutrophils to decrease inflammation-mediated damage after trauma
纳米颗粒介导的循环单核细胞和中性粒细胞重编程可减少创伤后炎症介导的损伤
- 批准号:
10212226 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
Nanoparticle-mediated reprogramming of circulating monocytes and neutrophils to decrease inflammation-mediated damage after trauma
纳米颗粒介导的循环单核细胞和中性粒细胞重编程可减少创伤后炎症介导的损伤
- 批准号:
10437650 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
Nanoparticle-mediated reprogramming of circulating monocytes and neutrophils to decrease inflammation-mediated damage after trauma
纳米颗粒介导的循环单核细胞和中性粒细胞重编程可减少创伤后炎症介导的损伤
- 批准号:
9978712 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
Nanoparticle-mediated reprogramming of circulating monocytes and neutrophils to decrease inflammation-mediated damage after trauma
纳米颗粒介导的循环单核细胞和中性粒细胞重编程可减少创伤后炎症介导的损伤
- 批准号:
10669080 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
Human neural stem cell therapy for the treatment of cervical spinal cord injury (
人类神经干细胞疗法治疗颈脊髓损伤(
- 批准号:
8503499 - 财政年份:2013
- 资助金额:
$ 45.03万 - 项目类别:
Human neural stem cell therapy for the treatment of cervical spinal cord injury (
人类神经干细胞疗法治疗颈脊髓损伤(
- 批准号:
8727119 - 财政年份:2013
- 资助金额:
$ 45.03万 - 项目类别:
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