Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases
Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases
批准号:
9764857
负责人:
Daryl Angela Bosco
金额:
$83.18万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-15 至 2024-03-31
关键词:
AffectAgeAgingAmyotrophic Lateral SclerosisAutopsyBiological ModelsBrainC9ORF72CalpainCell Culture TechniquesCell FractionationCell LineCell NucleusCellular StressChromatinClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexCytoplasmDNA DamageDNA-Binding ProteinsDataDefectDiseaseExhibitsFractionationGene ExpressionGenomicsGoalsHumanHuntington geneImpairmentIn VitroIndustrializationInheritedKnock-inKnock-in MouseLaboratoriesLiquid substanceLiteratureMediatingModelingMorphologyMotor NeuronsMusMutationNerve DegenerationNeurodegenerative DisordersNeuronsNuclearNuclear EnvelopeNuclear ExportNuclear PoreNuclear Pore ComplexNuclear Pore Complex ProteinsNucleocytoplasmic Transport ProteinsPathogenicityPathway interactionsPatientsPhasePhase TransitionPhenotypePore ProteinsProcessPropertyProteinsProteomeProteomicsPublishingRNARNA TransportRecombinant ProteinsResearchStressTestingTherapeuticTissuesToxic effectTranscriptage relatedcalpain inhibitorcell agedensityexportin 1 proteinfrontotemporal lobar dementia-amyotrophic lateral sclerosishuman diseaseinduced pluripotent stem cellindustry partnerinhibitor/antagonistinsightlink proteinmouse modelmutantnovelnucleocytoplasmic transporttherapeutic evaluationtherapeutic targettranscriptome sequencing
中文摘要
最近出现了蛋白质和RNA通过核孔的核质转运受损(NCT)
作为神经退化的中枢机制事实上,我们最近已经表明,突变亨廷顿蛋白显着
加剧衰老相关的核完整性改变和NCT破坏,以及核孔介导的
在C9 ORF 72相关的肌萎缩侧索硬化症(ALS)和额颞叶痴呆中也发现了转运
(FTD)。在这里,我们证明了突变FUS的表达,一种与ALS和FTD相关的蛋白质,导致细胞核的丢失,
孔完整性,改变的核膜形态和其他表型相关的破坏NCT在多个,相关
包括同基因人类神经元和一种新的FUS基因敲入小鼠模型。在这个项目中,我们将进一步
在ALS和FTD中,使用以下方法询问疾病相关FUS和NCT受损之间的关系:
上述模型系统和人CNS组织(目的1)。为了阐明表达的机制,
突变FUS诱导NCT相关表型,我们将进一步探讨FUS与核孔的相互作用
蛋白质,并测试的假设,异常相变涉及突变FUS和核孔蛋白
有助于破坏NCT(目标2)。我们还证实,受损的NCT诱导毒性通过错误定位的
转录物和蛋白质,这一概念将通过使用RNA测序和蛋白质组学来比较基因表达来进行测试
在突变FUS与对照神经元的细胞分级后,在NCT相关的表现之前和之后,
表型(目标3)。最后,我们将测试靶向FUS人类神经元核输出的治疗潜力,
小鼠使用已经被证明对多种人类疾病安全有效的策略(目标4)。
两个学术团体和一个工业合作伙伴(将提供治疗药物)之间的协同合作
在我们的实验室研究的化合物)有可能揭示新的机制见解的疾病和建立
ALS/FTD中靶向核质转运的治疗潜力。
英文摘要
Impaired nucleocytoplasmic transport (NCT) of protein and RNA through the nuclear pore has recently emerged
as a central mechanism in neurodegeneration. Indeed, we have recently shown that mutant huntingtin markedly
exacerbates aging-related alterations in nuclear integrity and disruption of NCT, and defects in nuclear pore-mediated
transport have also been uncovered in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
(FTD). Here, we demonstrate that expression of mutant FUS, a protein linked to ALS and FTD, leads to a loss of nuclear
pore integrity, altered nuclear envelope morphology and other phenotypes related to disrupted NCT in multiple, relevant
models including isogenic human neurons and a novel FUS knock-in mouse model. In this project, we will further
interrogate the relationship between disease-associated FUS and impaired NCT in ALS and FTD using the
aforementioned model systems and human CNS tissues (Aim 1). To elucidate the mechanism by which expression of
mutant FUS induces NCT-related phenotypes, we will further probe the interactions between FUS and nuclear pore
proteins, and test the hypothesis that abnormal phase transitions involving mutant FUS and nuclear pore proteins
contribute to disrupted NCT (Aim 2). We also posit that impaired NCT induces toxicity via the mislocalization of
transcripts and proteins, a notion that will be tested by using RNA-sequencing and proteomics to compare gene expression
after cellular fractionation in mutant FUS versus control neurons, before and after manifestation of NCT-related
phenotypes (Aim 3). Finally, we will test the therapeutic potential of targeting nuclear export in FUS human neurons and
mice using strategies that have already been shown to be both safe and effective across multiple human diseases (Aim 4).
This synergistic collaboration between two academic groups and an industrial partner (who will provide the therapeutic
compound for studies in our laboratories) has the potential to uncover new mechanistic insights to disease and establish
the therapeutic potential of targeting nucleocytoplasmic transport in ALS/FTD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Impact of ALS-linked mutations on the structure, dynamics and function of profilin-1
-
批准号:10323045
-
项目类别:
-
资助金额:$52.11万
-
财政年份:2021
-
负责人:Daryl Angela Bosco
-
依托单位:
Impact of ALS-linked mutations on the structure, dynamics and function of profilin-1
-
批准号:10533362
-
项目类别:
-
资助金额:$52.11万
-
财政年份:2021
-
负责人:Daryl Angela Bosco
-
依托单位:
Disruption of Nucleocytoplasmic Transport in FUS-related Neurodegenerative Diseases
-
批准号:10373038
-
项目类别:
-
资助金额:$79.04万
-
财政年份:2019
-
负责人:Daryl Angela Bosco
-
依托单位:
Disruption of Nucleocytoplasmic Transport in FUS-related Neurodegenerative Diseases
-
批准号:10601025
-
项目类别:
-
资助金额:$77.69万
-
财政年份:2019
-
负责人:Daryl Angela Bosco
-
依托单位:
Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases
-
批准号:10387048
-
项目类别:
-
资助金额:$8.68万
-
财政年份:2019
-
负责人:Daryl Angela Bosco
-
依托单位:
Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases
-
批准号:9927700
-
项目类别:
-
资助金额:$81.49万
-
财政年份:2019
-
负责人:Daryl Angela Bosco
-
依托单位:
Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases
-
批准号:10113372
-
项目类别:
-
资助金额:$80.65万
-
财政年份:2019
-
负责人:Daryl Angela Bosco
-
依托单位:
Misfolded ALS-linked Profilin-1: a novel therapeutic target
-
批准号:9277583
-
项目类别:
-
资助金额:$36.48万
-
财政年份:2014
-
负责人:Daryl Angela Bosco
-
依托单位:
Misfolded ALS-linked Profilin-1: a novel therapeutic target
-
批准号:9494711
-
项目类别:
-
资助金额:$36.48万
-
财政年份:2014
-
负责人:Daryl Angela Bosco
-
依托单位:
Misfolded ALS-linked Profilin-1: a novel therapeutic target
-
批准号:9084682
-
项目类别:
-
资助金额:$36.48万
-
财政年份:2014
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigating a Toxic Gain-of-Interaction Between FUS/TLS & Stress Granules
-
批准号:9021691
-
项目类别:
-
资助金额:$35.98万
-
财政年份:2012
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigating a Toxic Gain-of-Interaction Between FUS/TLS & Stress Granules
-
批准号:8274622
-
项目类别:
-
资助金额:$35.98万
-
财政年份:2012
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigating a Toxic Gain-of-Interaction Between FUS/TLS & Stress Granules
-
批准号:8443798
-
项目类别:
-
资助金额:$34.73万
-
财政年份:2012
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigating a Toxic Gain-of-Interaction Between FUS/TLS & Stress Granules
-
批准号:8636045
-
项目类别:
-
资助金额:$32.39万
-
财政年份:2012
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigating a Toxic Gain-of-Interaction Between FUS/TLS & Stress Granules
-
批准号:8817327
-
项目类别:
-
资助金额:$35.98万
-
财政年份:2012
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigation of post-translational modifications in WT SOD1 in sporadic ALS
-
批准号:8248066
-
项目类别:
-
资助金额:$35.26万
-
财政年份:2010
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigation of post-translational modifications in WT SOD1 in sporadic ALS
-
批准号:8447540
-
项目类别:
-
资助金额:$34.03万
-
财政年份:2010
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigation of post-translational modifications in WT SOD1 in sporadic ALS
-
批准号:8103952
-
项目类别:
-
资助金额:$35.26万
-
财政年份:2010
-
负责人:Daryl Angela Bosco
-
依托单位:
Investigation of post-translational modifications in WT SOD1 in sporadic ALS
-
批准号:7986420
-
项目类别:
-
资助金额:$35.98万
-
财政年份:2010
-
负责人:Daryl Angela Bosco
-
依托单位:
Oxidative metabolites in Alpha-Synucleinopathies
-
批准号:6999077
-
项目类别:
-
资助金额:$1.91万
-
财政年份:2005
-
负责人:Daryl Angela Bosco
-
依托单位:
国内基金
海外基金
登录
查看更多内容
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
-
批准号:JCZRLH202601523
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2026
-
负责人:
-
依托单位:
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
-
批准号:JCZRQN202500010
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:
-
依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
-
批准号:2025JJ70209
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:雷芬芳
-
依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
-
批准号:--
-
项目类别:面上项目
-
资助金额:--
-
批准年份:2024
-
负责人:万荣
-
依托单位:
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
-
批准号:2023JJ50274
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:贺志明
-
依托单位:
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
-
批准号:--
-
项目类别:地区科学基金项目
-
资助金额:33万元
-
批准年份:2022
-
负责人:都义日
-
依托单位:
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
-
批准号:--
-
项目类别:面上项目
-
资助金额:52万元
-
批准年份:2022
-
负责人:叶宝东
-
依托单位:
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:10.0万元
-
批准年份:2022
-
负责人:于海兵
-
依托单位:
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
-
批准号:81973577
-
项目类别:面上项目
-
资助金额:55.0万元
-
批准年份:2019
-
负责人:辛贵忠
-
依托单位:
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
-
批准号:81602908
-
项目类别:青年科学基金项目
-
资助金额:18.0万元
-
批准年份:2016
-
负责人:刘括
-
依托单位: