In vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathies
TDP-43 蛋白病中 stathmin-2 缺失的体内建模和治疗开发
基本信息
- 批准号:10317404
- 负责人:
- 金额:$ 250.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAllelesAlzheimer&aposs disease patientAmyotrophic Lateral SclerosisAnimal ModelAnimalsAntisense OligonucleotidesAxonAxotomyBindingBinding ProteinsBinding SitesC9ORF72ChronicCognition DisordersCollaborationsCytoplasmDiseaseFrontotemporal DementiaGenesGenetically Engineered MouseHumanIndustrializationInheritedInjectionsIntronsLeadMaintenanceMediatingMessenger RNAModelingMolecularMotorMotor NeuronsMusMutationNatural regenerationNerve DegenerationNerve RegenerationNervous system structureNeurodegenerative DisordersNeuromuscular JunctionNeuronsNuclearPGRN genePathogenesisPathologicPathologyPatientsPhenotypePolyadenylationPre-Clinical ModelProteinsRNARNA ProcessingRNA SplicingRNA-Binding ProteinsRegenerative capacityRodentRoleSiteSpinal CordTestingTherapeuticTissuesTranscriptalpha Tubulinaxon regenerationbasefallsfamilial amyotrophic lateral sclerosisfrontotemporal lobar dementia-amyotrophic lateral sclerosisgenome editinggranulinhumanized mousein vivoin vivo Modelin vivo evaluationinduced pluripotent stem cellinsightloss of functionmRNA Precursormodel developmentmotor deficitmouse genomemouse modelnervous system disorderneuronal growthnovel therapeutic interventionprematurepreventprogramsprotein TDP-43restorationsmall hairpin RNAsporadic amyotrophic lateral sclerosisstathmintherapeutic developmenttherapeutic effectivenesstherapeutic evaluationtherapy development
项目摘要
PROJECT SUMMARY
TDP-43 proteinopathies represent a set of neurological disorders characterized by relocalization of the RNA-
binding protein TDP-43 from its native nuclear compartment to the cytoplasm where it accumulates into
aggregates. TDP-43 pathology is found in more than 95% of patients with amyotrophic lateral sclerosis (ALS),
approximately half of frontotemporal dementia (FTD) cases, and more than 30% of Alzheimer’s disease patients.
TDP-43 is involved in fundamental RNA processing activities and binds thousands of transcripts to regulate their
expression, splicing and transport. We and others have recently identified a critical role for TDP-43 in regulating
the expression of the neuronal growth-associated factor stathmin-2, a tubulin-binding protein involved in axon
outgrowth and regeneration. TDP-43 disruption induces truncation (by aberrant splicing and premature
polyadenylation) of stathmin-2 pre-mRNA, thereby silencing stathmin-2 when TDP-43 nuclear levels fall.
Stathmin-2 is suppressed in affected neurons from the vast majority of ALS/FTD patients, and the neuronal
regeneration capacity of iPSC-derived motor neurons with TDP-43 depletion can be rescued by increasing levels
of STMN2. Notably, while stathmin-2 is the human mRNA most affected by reduction in TDP-43, the stahmin-2
pre-mRNA is neither bound nor regulated by TDP-43 in rodents, a major caveat for animal modeling of TDP-43
proteinopathies. Here we propose to use newly generated mouse models to determine whether inactivated (Aim
1) or humanized stathmin-2 (Aim 2) alleles synergize with TDP-43, progranulin, or C9ORF72 ALS/FTD
mutations to drive motor neuron or cognitive disease. While evidence supports that stathmin-2 is essential for
axonal regeneration, the contribution of stathmin-2 loss in neurodegeneration remains to be determined. We
propose an ambitious program to establish the impact of in vivo stathmin-2 reduction in TDP-43 proteinopathies.
Mouse models generated in this project will recapitulate a major molecular alteration associated with TDP-43
proteinopathy and represent an important platform for therapeutic development in ALS/FTD. In addition,
recognizing that restoration of stathmin-2 level is an attractive strategy with broad implications in
neurodegenerative diseases, we will test the therapeutic potential of antisense oligonucleotides (ASO) that
prevent aberrant splicing of Stmn2 (Aim 3). This collaborative effort has the potential to uncover new insights on
the contribution of stathmin-2 loss in neurodegeneration, to generate new preclinical models, and to develop a
novel therapeutic strategy for ALS and FTD.
项目总结
TDP-43蛋白病代表了一组以RNA-43重新定位为特征的神经系统疾病。
结合蛋白TDP-43从其天然核室到细胞质,在那里它积聚成
集合体。在超过95%的肌萎缩侧索硬化症(ALS)患者中发现了TDP-43病理,
大约一半的额颞叶痴呆(FTD)患者和超过30%的阿尔茨海默病患者。
TDP-43参与基本的RNA加工活动,并结合数千个转录本来调节其
表达、剪接和运输。我们和其他人最近确定了TDP-43在调节
参与轴突的微管蛋白结合蛋白神经元生长相关因子Stathmin-2的表达
生长和再生。TDP-43中断导致截断(通过异常剪接和过早
多聚腺苷酸化),从而在TDP-43核水平下降时沉默stathmin-2。
在绝大多数ALS/FTD患者的受影响神经元中,stathmin-2受到抑制,神经元
TDP-43缺失的IPSC来源运动神经元的再生能力可通过提高水平来挽救
STMN2.值得注意的是,虽然stathmin-2是受TDP-43减少影响最大的人mRNA,但stahmin-2
在啮齿动物中,前-mRNA既不受TDP-43的结合,也不受TDP-43的调节,这是TDP-43动物模型的主要警告
蛋白质病。在这里,我们建议使用新生成的小鼠模型来确定灭活(Aim
1)或人源化的stathmin-2(Aim 2)等位基因与TDP-43、原颗粒蛋白或C9ORF72 ALS/FTD协同作用
突变以驱动运动神经元或认知疾病。虽然有证据支持stathmin-2对
轴突再生,Stathmin-2缺失在神经退行性变中的作用仍有待确定。我们
提出一项雄心勃勃的计划,以确定体内stathmin-2减少对TDP-43蛋白病变的影响。
在这个项目中产生的小鼠模型将概括与TDP-43相关的主要分子改变
蛋白质病,是ALS/FTD治疗发展的重要平台。此外,
认识到恢复stathmin-2水平是一项有吸引力的战略,在#年具有广泛影响
神经退行性疾病,我们将测试反义寡核苷酸(ASO)的治疗潜力
防止Stmn2的异常剪接(目标3)。这一合作努力有可能发现以下方面的新见解
Stathmin-2缺失在神经退行性变中的作用,产生新的临床前模型,并发展一种
ALS和FTD的新治疗策略。
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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Don W Cleveland其他文献
Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease
胶质细胞作为非细胞自主性神经退行性疾病的内在成分
- DOI:
10.1038/nn1988 - 发表时间:
2007-10-26 - 期刊:
- 影响因子:20.000
- 作者:
Christian S Lobsiger;Don W Cleveland - 通讯作者:
Don W Cleveland
VEGF: multitasking in ALS
血管内皮生长因子:在肌萎缩侧索硬化症中的多任务处理
- DOI:
10.1038/nn0105-5 - 发表时间:
2005-01-01 - 期刊:
- 影响因子:20.000
- 作者:
Christine Vande Velde;Don W Cleveland - 通讯作者:
Don W Cleveland
Don W Cleveland的其他文献
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{{ truncateString('Don W Cleveland', 18)}}的其他基金
Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD
确定 Stathmin-2 的功能和作为 ALS/FTD 治疗靶点的潜力
- 批准号:
10835733 - 财政年份:2020
- 资助金额:
$ 250.73万 - 项目类别:
Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD
确定 Stathmin-2 的功能和作为 ALS/FTD 治疗靶点的潜力
- 批准号:
10370327 - 财政年份:2020
- 资助金额:
$ 250.73万 - 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
- 批准号:
10674798 - 财政年份:2017
- 资助金额:
$ 250.73万 - 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
- 批准号:
9883009 - 财政年份:2017
- 资助金额:
$ 250.73万 - 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
- 批准号:
10406521 - 财政年份:2017
- 资助金额:
$ 250.73万 - 项目类别:
Junior Faculty and Postdoctoral Fellows Career Development Workshop
初级教师和博士后研究员职业发展研讨会
- 批准号:
8720394 - 财政年份:2014
- 资助金额:
$ 250.73万 - 项目类别:
POST-TRANSLATIONAL MODIFICATION AND INTERACTING PROTEINS OF CENP-E
CENP-E 的翻译后修饰和相互作用蛋白
- 批准号:
8171370 - 财政年份:2010
- 资助金额:
$ 250.73万 - 项目类别:
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