Targeting Rab6-km23-1-mediated compartmentalized trafficking as a novel therapeutic approach to Alzheimers Disease
靶向 Rab6-km23-1 介导的区室化运输作为阿尔茨海默病的新型治疗方法
基本信息
- 批准号:9756263
- 负责人:
- 金额:$ 19.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAmyloid beta-Protein PrecursorAnimal ModelAreaBindingBrainC-terminalCarrier ProteinsCell modelCellsClinical TrialsComplexComputer SimulationDNA Sequence AlterationDendritesDown SyndromeDrug TargetingDynein ATPaseEndosomesEngineeringEnzymesEventFailureFamilyFunctional disorderGolgi ApparatusGrowthHippocampus (Brain)Hot SpotHumanIndividualLeadLightLocationMAP Kinase GeneMediatingMediator of activation proteinModelingMotorMusMutationNerveNeuritesNeuronsOrganellesOutcomePaintPathogenesisPathologyPathway interactionsPatientsPeptidesPlayPresenile Alzheimer DementiaPrevention strategyProcessProductionProtein FamilyProtein FragmentProtein RegionProteinsProteolysisRecyclingRegulationRodentRoleRouteSenile PlaquesSignal TransductionSiteSorting - Cell MovementStructural ModelsSurfaceSynapsesTechnologyTestingTherapeuticTherapeutic AgentsTransport VesiclesVesicleVesicle Transport Pathwayalpha secretaseamyloid peptideamyloid precursor protein processingaxonopathybasebeta secretasebeta-site APP cleaving enzyme 1designdisease phenotypefamilial Alzheimer diseasehuman modelinduced pluripotent stem cellinhibitor/antagonistlink proteinmembermutantneuron lossneuronal cell bodynext generationnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspeptide drugpreventprotein complexprotein protein interactionprotein transportrab GTP-Binding Proteinsretrograde transportspatiotemporalsynthetic peptidetargeted treatmenttherapeutic targettrafficking
项目摘要
Summary
The amyloid hypothesis as the cause for Alzheimer's Disease (AD) has recently come under fire due to the
failure of so many clinical trials for amyloid peptide (Aß)-targeting therapies. However, it may be that amyloid
precursor protein (APP) itself, or the C-terminal fragment-ß (CTFß) produced by ß-secretase (BACE1)
cleavage, is the actual culprit in AD, having a more direct role in AD than previously thought. In the current
proposal, we will study a novel approach to reducing early-stage AD by targeting the protein-protein interaction
of a complex (km23-1–Rab6) that we propose controls the trafficking of APP and the rate-limiting enzyme
(BACE1) in APP processing. More specifically, we will test the novel hypothesis that APP and BACE1 are
transported in km23-1–Rab6 vesicles to the Golgi, where CTFß is produced to play a role in neurite outgrowth
and dendritic branching. We hypothesize, further, that APP or CTFß accumulation here in AD causes
exuberant and aberrant hippocampal axodentritic sprouting, eventually leading to diminish dendritic arbor
complexity and breakage of neuronal branches. We will examine the km23-1–Rab6-mediated transport of APP
and BACE1 to the Golgi, as well as the effects of the resulting APP fragments on dendritic branching. The
results will provide a stronger basis for targeting the physical association of APP and BACE1 at Golgi sites, to
reduce BACE1 activity and the subsequent production of APP intermediates. Α greater understanding of the
mechanisms underlying km23-1–Rab6 regulation of APP and BACE1 interactions at the Golgi to control
dendritic arborization should facilitate targeting this key trafficking event to reduce early AD-associated causal
events.
Our structural modeling of the km23-1–Rab6 complex revealed “hot spots” for the precise sites of protein-
protein interaction. In Aim 1, we will examine the effects of site-specific mutants of the proteins on the
spatiotemporal regulation of km23-1–Rab6 complexes, as well as on APP/BACE1 association and
compartment location. The focus will be on APP and BACE1 association at soma Golgi, as well as at Golgi
outposts (GOs) in developing dendrites, in order to better understand the mechanisms underlying APP
trafficking, processing, and signaling at these specific regions. In Aims 2 and 3, we will us in silico modeling
and apply a novel Protein Painting technology to reveal the unique interface by which km23-1 interacts with
Rab6 in regulating APP trafficking and processing. The precise interaction region will be used to design
corresponding peptide inhibitors to be tested for inhibitory effects on km23-1–Rab6 complex formation, APP
processing, and AD-associated pathologies. While the majority of previous studies have used rodent familial
AD (FAD) models, here we will apply human models that recapitulate sporadic AD (sAD) to test our novel
km23-1–Rab6 inhibitors. The use of the hidden contact regions between these critical interacting proteins as
drug targets will lead to paradigm-shifting therapies, overcoming the limitations with past therapeutic strategies.
The novel therapeutic agents for AD developed as a result of the proposed studies will be among critical
members of the next generation of AD-targeted therapeutics.
总结
项目成果
期刊论文数量(0)
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Lance Allen Liotta其他文献
Lance Allen Liotta的其他文献
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{{ truncateString('Lance Allen Liotta', 18)}}的其他基金
Protein painting identifies therapeutic targets at protein-protein interfaces
蛋白质绘画识别蛋白质-蛋白质界面的治疗靶点
- 批准号:
9392299 - 财政年份:2016
- 资助金额:
$ 19.14万 - 项目类别:
Protein painting identifies therapeutic targets at protein-protein interfaces
蛋白质绘画识别蛋白质-蛋白质界面的治疗靶点
- 批准号:
9338200 - 财政年份:2016
- 资助金额:
$ 19.14万 - 项目类别:
Probes to target the 3-way hotspot of IL1RacP to abolish aberrant interleukin inflammation
靶向 IL1RacP 3 路热点以消除异常白细胞介素炎症的探针
- 批准号:
9085212 - 财政年份:2015
- 资助金额:
$ 19.14万 - 项目类别:
Probes to target the 3-way hotspot of IL1RacP to abolish aberrant interleukin inflammation
靶向 IL1RacP 3 路热点以消除异常白细胞介素炎症的探针
- 批准号:
8944833 - 财政年份:2015
- 资助金额:
$ 19.14万 - 项目类别:
Protein Painting reveals hidden protein-protein interaction domains
蛋白质绘画揭示了隐藏的蛋白质-蛋白质相互作用域
- 批准号:
8728792 - 财政年份:2013
- 资助金额:
$ 19.14万 - 项目类别:
Protein Painting reveals hidden protein-protein interaction domains
蛋白质绘画揭示了隐藏的蛋白质-蛋白质相互作用域
- 批准号:
8547427 - 财政年份:2013
- 资助金额:
$ 19.14万 - 项目类别:
Nanotrap technology for one step preservation and amplification of cancer biomark
Nanotrap 技术可一步保存和扩增癌症生物标志物
- 批准号:
8548317 - 财政年份:2012
- 资助金额:
$ 19.14万 - 项目类别:
Nanotrap technology for one step preservation and amplification of cancer biomark
Nanotrap 技术可一步保存和扩增癌症生物标志物
- 批准号:
8433072 - 财政年份:2012
- 资助金额:
$ 19.14万 - 项目类别:
Nanotrap technology for one step preservation and amplification of cancer biomark
Nanotrap 技术可一步保存和扩增癌症生物标志物
- 批准号:
8723137 - 财政年份:2012
- 资助金额:
$ 19.14万 - 项目类别:
Implementation of phosphoprotein preservation technology for cancer biospecimens
癌症生物样本磷蛋白保存技术的实现
- 批准号:
8311650 - 财政年份:2011
- 资助金额:
$ 19.14万 - 项目类别: