The Role of RNA Binding Protein Networks in Tauopathy and Related Dementia
RNA 结合蛋白网络在 Tau 病和相关痴呆中的作用
基本信息
- 批准号:10034785
- 负责人:
- 金额:$ 309.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingAlternative SplicingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAnimal ModelBiochemicalBioinformaticsBiological AssayBrainBrain regionCell LineComplexCustomDataData SetDegenerative DisorderDementiaDiseaseElementsExonsFrontotemporal Lobar DegenerationsFutureGene ExpressionGene Expression RegulationGene ProteinsGenesGenetic TranscriptionGenetic studyGoalsHumanImpaired cognitionIndividualIntronsKnock-inKnock-in MouseLeadMessenger RNAMethodsModelingMolecularMultiomic DataNatureNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathogenicityPathologicPathologyPatientsPlayProtein IsoformsProteomicsPublic HealthPublishingRNARNA SplicingRNA analysisRNA-Binding ProteinsRegulationRegulator GenesRoleSamplingSocietiesSpliceosomesTauopathiesTestingWorkbasecognitive functioncohortdesigngene productgenetic regulatory proteinin vivoindexinginduced pluripotent stem cellinnovationinsightinterdisciplinary approachmRNA ExpressionmRNA Precursormouse modelneurotoxicitynovel diagnosticsnovel therapeuticsprotein expressionresiliencerisk varianttau Proteinstau aggregationtau expressiontherapeutic developmenttooltranscriptome sequencingtreatment strategy
项目摘要
The Role of RNA Binding Protein Networks in Tauopathy and Related Dementia
Dementias, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and
related diseases, become a leading challenge in our progressively aging society. The presence of
tau protein-containing neurofibrillary tangles is a major neuropathological hallmark of AD and
related dementia. Although RNA binding proteins (RBPs) are emerging as critical players in these
neurodegenerative diseases, little is known about the RBP networks that control the balanced
expression of the human tau gene or other dementia-associated genes (DAGs). Based on
published studies and preliminary data, we propose to test the hypotheses that the RBP-tau
regulatory networks that maintain balanced tau alternative splicing and tau mRNA expression are
disrupted in tauopathies, leading to aberrant tau splicing and contributing to pathological tau
aggregation and neurodegeneration. We plan to leverage the vast RNA-seq and proteomics data
to construct RBP-tau gene regulatory networks and to use the newly developed human Tau knock-
in (hTauKI) mouse model together with patient samples and iPSC neurons to validate key players
contributing to the pathogenesis of dementia and related tauopathies. We will determine RBP
genes and networks affected in dementia by examining candidate AD-associated RBPs in
independent cohorts of patient samples using combined bioinformatics and molecular approaches
(Aim 1). We will characterize RBP-tau RNA interactome using the hTauKI mice and using iPSC-
derived neurons (Aim 2). We will determine the role of RBP-tau regulatory networks in tau
neurotoxicity by dissecting molecular mechanisms of candidate RBPs in regulating tau pre-mRNA
splicing and in tau pathogenesis (Aim 3). Our integrated multi-disciplinary approach combines
bioinformatics with state-of-art molecular/biochemical assays with the brand-new hTauKI mouse
model and iPSC-derived human neurons. This will enable us to construct RBP-tau regulatory
networks critical for normal brain function and for tau pathogenesis. The proposed study will not
only advance our understanding of complex post-transcriptional mechanisms regulating expression
of DAGs and provide mechanistic insights into the function of RBP-tau networks, but also lead to
information useful for developing new diagnostic and therapeutic tools for dementia.
RNA结合蛋白网络在Tau病及相关痴呆中的作用
痴呆,包括阿尔茨海默病(AD)、额颞叶变性(FTLD)和阿尔茨海默病(AD)。
在我们这个日益老龄化的社会中,与疾病相关的疾病成为一个主要挑战。的存在
含tau蛋白的神经元缠结是AD的主要神经病理学标志,
痴呆症相关尽管RNA结合蛋白(RBP)正在成为这些领域的关键参与者,
神经退行性疾病,很少有人知道RBP网络控制的平衡
人tau基因或其它痴呆相关基因(DAG)的表达。基于
根据已发表的研究和初步数据,我们建议测试RBP-tau蛋白
维持平衡的tau可变剪接和tau mRNA表达的调控网络,
在tau蛋白病中被破坏,导致异常的tau剪接并促成病理性tau蛋白
聚集和神经变性。我们计划利用大量的RNA测序和蛋白质组学数据
构建RBP-tau基因调控网络,并使用新开发的人Tau敲除-
在(hTauKI)小鼠模型中与患者样品和iPSC神经元一起验证关键参与者
导致痴呆和相关的tau蛋白病的发病机制。我们将确定RBP
通过检查候选AD相关RBP,
使用组合的生物信息学和分子方法的患者样本的独立群组
(Aim 1)。我们将使用hTauKI小鼠和使用iPSC表征RBP-tau RNA相互作用组。
衍生神经元(Aim 2)。我们将确定RBP-tau调控网络在tau蛋白中的作用,
通过剖析候选RBP在调节tau前mRNA中的分子机制的神经毒性
剪接和tau发病机制(Aim 3)。我们的综合多学科方法结合了
使用全新hTauKI小鼠进行最先进的分子/生物化学测定的生物信息学
模型和iPSC衍生的人类神经元。这将使我们能够构建RBP-tau调控
网络对于正常脑功能和tau发病机制至关重要。拟议的研究将不
这只会促进我们对复杂的转录后机制的理解,
的DAG,并提供对RBP-tau网络功能的机械见解,但也导致
这些信息有助于开发痴呆症的新诊断和治疗工具。
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 }}
ROBERT J VASSAR其他文献
ROBERT J VASSAR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('ROBERT J VASSAR', 18)}}的其他基金
Mechanisms of Angiotensin I Converting Enzyme in Alzheimer's disease
血管紧张素I转换酶在阿尔茨海默病中的作用机制
- 批准号:
10568226 - 财政年份:2022
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10469445 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10264367 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10662473 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
Northwestern ADRC Non competing supplement application
西北 ADRC 非竞争性补充申请
- 批准号:
10577047 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
2nd Kloster Seeon Meeting on BACE Proteases in Health and Disease
关于 BACE 蛋白酶在健康和疾病中的作用的第二届 Kloster Seeon 会议
- 批准号:
9195559 - 财政年份:2016
- 资助金额:
$ 309.02万 - 项目类别:
Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease
阿尔茨海默氏病 BACE1 升高的分子神经病理学和机制
- 批准号:
7248235 - 财政年份:2007
- 资助金额:
$ 309.02万 - 项目类别:
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Collaborative R&D
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Operating Grants
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
- 批准号:
23K20355 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
- 批准号:
23K24782 - 财政年份:2024
- 资助金额:
$ 309.02万 - 项目类别:
Grant-in-Aid for Scientific Research (B)