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:9241460
- 负责人:
- 金额:$ 33.79万
- 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 2021-03-31
- 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 GranulesDataDevelopmentFailureFamilyGeneticGillsHumanHuman DevelopmentIn Situ Nick-End LabelingIn VitroInjuryKnock-outKnockout MiceLampreysLeadLesionLeukocytesLinkMammalsMediatingModelingMonomeric GTP-Binding ProteinsMusNatural regenerationNerve CrushNerve FibersNeuraxisNeuronsOptic NervePTEN geneParalysedPathway interactionsPeptidesPharmacologyProceduresProtein InhibitionProtein Tyrosine PhosphataseReceptor InhibitionRetinal Ganglion CellsRodentSignal TransductionSiteSpinalSpinal GangliaSpinal cord injuryTestingTimeTransferaseWestern Blottingaxon growthaxon regenerationcentral nervous system injuryexperimental studyganglion cellin vivoinhibitor/antagonistinjuredknock-downloss of functionmRNA Expressionmanneuron 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.
描述(由申请人提供):人类脊髓损伤(SCI)导致永久性瘫痪,因为受损的神经纤维(轴突)不能再生。其中一个原因是损伤附近的细胞分泌硫酸软骨素蛋白聚糖(CSPG)。CSPG与蛋白酪氨酸磷酸酶(RPTP)家族的受体PTPσ和LAR结合,并抑制轴突生长。脊髓损伤后的再生在七鳃鳗中更成功,但一些已鉴定的网状脊髓(RS)神经元是不良的再生者,当它们的轴突受损时,这些神经元经历非常延迟的程序性细胞死亡(凋亡)。我们将确定CSPG是否通过PTPσ和/或LAR起作用,既抑制真正的轴突再生(与未损伤轴突的发芽相反),又触发SCI后的逆行凋亡。我们将测试用软骨素酶(ChABC)消化CSPG是否会增加脊髓投射神经元的存活和/或其轴突的再生,以及添加外源性CSPG是否会产生相反的效果。体外证据表明,CSPG通过LAR激活小GT3 RhoA和Akt。这两种信号都有下游效应,可以抑制轴突生长。通过阻断RhoA的合成或激活并观察对Akt活性的影响,我们将确定对Akt的影响是否在RhoA的下游,或者这两条通路是否是独立触发的,也许是由不同的RPTP触发的。将吗啉代反义寡核苷酸(MOs)从损伤部位逆行递送至RS神经元将抑制RhoA的合成。RhoA的激活将被C3转移酶阻断。将确定对细胞凋亡标志物和轴突再生的影响。RPTP的合成也将被MO抑制,以确定哪种受体介导CSPG的哪种负面作用。为了测试七鳃鳗中的效应是否也适用于哺乳动物神经元,我们将对出生后和成年哺乳动物原代神经元培养物进行平行实验。我们还将在小鼠视神经挤压模型中测试RPTP的遗传敲除或药理学抑制是否减少逆行神经元死亡并增强体内视网膜神经节细胞的轴突再生。了解介导CSPG对细胞存活和轴突再生的抑制作用的细胞内途径可能会导致人类SCI治疗的发展。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MICHAEL EDGAR SELZER其他文献
MICHAEL EDGAR SELZER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
9311288 - 财政年份:2017
- 资助金额:
$ 33.79万 - 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:
9903455 - 财政年份:2017
- 资助金额:
$ 33.79万 - 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:
9903453 - 财政年份:2016
- 资助金额:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 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:
$ 33.79万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 33.79万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 33.79万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 33.79万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 33.79万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 33.79万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)