Nanobodies targeting stress granule components
针对应激颗粒成分的纳米抗体
基本信息
- 批准号:10739370
- 负责人:
- 金额:$ 46.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAmyloidosisAmyotrophic Lateral SclerosisAnimal ModelAnimalsAstrocytesBindingBinding ProteinsBiologicalBrainCellsChronic stressCytoplasmDNADetectionDirected Molecular EvolutionDiseaseEnvironmentExhibitsFrontotemporal DementiaFunctional disorderGelGoalsHippocampusHumanImageImmunityImmunoglobulin FragmentsIn VitroInduced pluripotent stem cell derived neuronsInvestigationKineticsKnowledgeLinkLiquid substanceMethodsMicrogliaModificationMolecular ProfilingMonitorMusMutationNatureNerve DegenerationNervous SystemNeurodegenerative DisordersNeuronsPathogenesisPathologicPathologyPathway interactionsPatternPhasePhysical condensationPlasmid Cloning VectorPlayPropertyProteinsProteomicsRNARNA DegradationRNA metabolismRNA methylationRNA-Binding ProteinsReagentRoleSolidSpecificityTauopathiesTestingTimeTissuesValidationViralViral VectorVirusbiological adaptation to stresscell typecomplex biological systemshigh throughput screeninghuman pluripotent stem cellimprovedin vivoin vivo imaginginduced pluripotent stem cellinsightinterestlipid metabolismnanobodiesnovelprotein TDP-43responsescreeningstem cell modelstress granulestress reductionsuccesstau Proteinstau aggregationthree-dimensional modelingtooltranscriptomicsubiquitin-protein ligase
项目摘要
Transcriptomic and proteomic studies on AD/ADRD consistently show alterations of pathways involved in
immunity, lipid metabolism, tau-binding protein network, and RNA metabolism. Recent advances in
understanding the proteins involved in RNA metabolism, including RNA-binding proteins (RBPs) involved in
stress granule (SG) formation provided new insights into the pathogenesis of AD. SGs formed of RNA and RBPs
such as TDP-43, hnRNPA2B1, and TIA1 are biomolecular condensates (BMCs) that can form a separate liquid
phase in cells. Mislocalization of RBPs to the cytoplasm increases the liquid-liquid phase separation (LLPS)
propensity, leading to increased SG formation. Under chronic stress, the SGs mature into a more solid or gel-
like assembly, sequestering the SG components. Over the past years, we and others have identified the
sequestration of RBPs as a critical mechanism of dysfunction in frontotemporal dementia-TDP-43, ALS, and AD.
We discovered that stress response is linked to oligomeric tau (o-tau) accumulation through the RBP
hnRNPA2B1, which preferentially interacts with tau when it is oligomerized. Since hnRNPA2B1 binds to the m6A
RNA methylation, this study also revealed the relevance of RNA modification in AD. As the interest in RBPs and
SGs grows, there is an increasing need to validate these assemblies in vivo. However, we lack the ability to
monitor SG dynamics without altering the intracellular concentration of SG components. We hypothesize that
endogenous SG components can be detected without perturbing their LLPS propensity through specific,
monovalent binders to SG components. Here we demonstrate for the first time that nanobodies (Nbs), single-
domain intracellular binding proteins, specific to RBPs can be identified through a high-throughput screen
approach. We aim to use the Nbs to detect SG components without altering their intracellular concentration and
demonstrate their use in a novel 3D human induced pluripotent stem cell (iPSC) model of AD that recapitulates
the tau-associated SG pathogenesis. We also demonstrate targeted degradation of hnRNPA2B1 using Nb fused
to an E3 ligase adaptor domain, and aim to validate the reversibility of SGs in primary neurons and the 3D human
iPSC model. Finally, we will screen Nbs specific to the m6A RNA methylation to enable imaging m6A RNA
methylation in SGs.
AD/ADRD的转录组学和蛋白质组学研究一致显示参与的通路改变
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)
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Yongku Peter Cho其他文献
Yongku Peter Cho的其他文献
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{{ truncateString('Yongku Peter Cho', 18)}}的其他基金
A synthetic biology approach for tau post-translational modifications in AD
AD 中 tau 翻译后修饰的合成生物学方法
- 批准号:
10739891 - 财政年份:2023
- 资助金额:
$ 46.08万 - 项目类别:
EARLY DETECTION OF TAU ACETYLATION USING ULTRA-HIGH AFFINITY ANTIBODIES
使用超高亲和力抗体早期检测 TAU 乙酰化
- 批准号:
9227696 - 财政年份:2016
- 资助金额:
$ 46.08万 - 项目类别:
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