CSPG-induced retrograde cell death and inhibition of regeneration after SCI
CSPG 诱导 SCI 后逆行细胞死亡和再生抑制
基本信息
- 批准号:9903453
- 负责人:
- 金额:$ 33.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAnimalsAntisense OligonucleotidesApoptosisApoptoticAxonAxotomyBindingCASP8 geneCell DeathCell Death InhibitionCell SurvivalCellsCessation of lifeChondroitin ABC LyaseChondroitin Sulfate ProteoglycanChondroitinasesCytoplasmic GranulesDataDevelopmentFailureFamilyGeneticGillsHumanIn Situ Nick-End LabelingIn VitroInjuryKnock-outKnockout MiceLampreysLeadLesionLeukocytesLinkMammalsMediatingModelingMonomeric GTP-Binding ProteinsMusNatural regenerationNerve CrushNerve FibersNeuraxisNeuronsOptic NervePTEN geneParalysedPathway interactionsPeptidesPharmacologyProceduresProtein Tyrosine PhosphataseReceptor InhibitionRetinal Ganglion CellsRodentSignal TransductionSiteSpinalSpinal GangliaSpinal cord injuryTestingTimeTransferaseWestern Blottingaxon growthaxon injuryaxon regenerationcell regenerationcentral nervous system injuryexperimental studyganglion cellin vivoinhibitor/antagonistinjuredknock-downloss of functionmRNA Expressionmannerve injuryneuron losspostnatalpublic health relevancereceptorregenerative therapytherapy developmenttyrosine receptor
项目摘要
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) in humans leads to permanent paralysis because injured nerve fibers (axons) do not regenerate. One reason for this is the secretion of chondroitin sulfate proteoglycans (CSPGs) by cells near the injury. CSPGs bind to receptors of the protein tyrosine phosphatase (RPTP) family, PTPσ and LAR, and inhibit axon growth. Regeneration after SCI is more successful in lampreys, but some identified reticulospinal (RS) neurons are bad regenerators, and when their axons are injured, these undergo very delayed programmed cell death (apoptosis). We will determine whether, acting through PTPσ and/or LAR, CSPGs both inhibit true axon regeneration (as opposed to sprouting by uninjured axons) and trigger retrograde apoptosis after SCI. We will test whether digesting CSPGs with chondroitinase (ChABC) increases survival of spinal-projecting neurons and/or regeneration of their axons, and whether adding extrinsic CSPGs has the opposite effects. Evidence in vitro suggests that CSPGs, acting through LAR activate the small GTPase RhoA and inactivate Akt. Both signals have downstream effects that could inhibit axon growth. By blocking RhoA synthesis or activation and observing the effect on Akt activity, we will determine whether the effect on Akt is downstream of RhoA, or whether the two pathways are triggered independently, perhaps by different RPTPs. RhoA synthesis will be inhibited with morpholino antisense oligonucleotides (MOs) delivered to RS neurons retrogradely from the injury site. Activation of RhoA will be blocked with C3 transferase. The effect on apoptosis markers and axon regeneration will be determined. Synthesis of the RPTPs also will be inhibited with MOs, to determine which receptor mediates which of the negative effects of CSPGs. To test whether effects in lampreys also apply to mammalian neurons, we will perform parallel experiments on postnatal and adult mammalian primary neuronal cultures. We also will test in a mouse optic nerve crush model, whether genetic knockdown or pharmacological inhibition of RPTPs reduces retrograde neuronal death and enhances axonal regeneration in retinal ganglion cells in vivo. Understanding the intracellular pathways that mediate the inhibitory effects of CSPGs on cell survival and axon regeneration could lead to development of therapies for human SCI.
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Effect of Axon Resealing on Retrograde Neuronal Death after Spinal Cord Injury in Lamprey.
- DOI:10.3390/brainsci8040065
- 发表时间:2018-04-14
- 期刊:
- 影响因子:3.3
- 作者:Zhang G;Rodemer W;Lee T;Hu J;Selzer ME
- 通讯作者:Selzer ME
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MICHAEL EDGAR SELZER其他文献
MICHAEL EDGAR SELZER的其他文献
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{{ truncateString('MICHAEL EDGAR SELZER', 18)}}的其他基金
Role of Local Protein Synthesis in CNS Axon Regeneration
局部蛋白质合成在中枢神经系统轴突再生中的作用
- 批准号:
9903455 - 财政年份:2017
- 资助金额:
$ 33.76万 - 项目类别:
Role of Local Protein Synthesis in CNS Axon Regeneration
局部蛋白质合成在中枢神经系统轴突再生中的作用
- 批准号:
9311288 - 财政年份:2017
- 资助金额:
$ 33.76万 - 项目类别:
CSPG-induced retrograde cell death and inhibition of regeneration after SCI
CSPG 诱导 SCI 后逆行细胞死亡和再生抑制
- 批准号:
9241460 - 财政年份:2016
- 资助金额:
$ 33.76万 - 项目类别:
CSPG-induced retrograde cell death and inhibition of regeneration after SCI
CSPG 诱导 SCI 后逆行细胞死亡和再生抑制
- 批准号:
9106726 - 财政年份:2016
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
8076619 - 财政年份:2009
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
7490398 - 财政年份:2005
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
8547941 - 财政年份:2005
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
6985934 - 财政年份:2005
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
7121577 - 财政年份:2005
- 资助金额:
$ 33.76万 - 项目类别:
Center for experimental neurorehabilitation training
实验神经康复训练中心
- 批准号:
7271249 - 财政年份:2005
- 资助金额:
$ 33.76万 - 项目类别:
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