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.
摘要
淀粉样蛋白假说作为阿尔茨海默病(AD)的原因最近受到了抨击,因为
如此多的淀粉样肽(A?)靶向治疗的临床试验失败。然而,可能是淀粉样蛋白
前体蛋白(APP)本身,或分泌酶(BACE1)产生的C-末端片段(CTF?)
乳沟是AD的真正罪魁祸首,它在AD中的作用比之前认为的更直接。在当前
建议,我们将研究一种新的方法,通过靶向蛋白质-蛋白质相互作用来减少早期AD
我们提出的一种复合体(km23-1-Rab6)控制APP的转运和限速酶
(BACE1)在应用处理中。更具体地说,我们将测试APP和BACE1是
在km23-1-Rab6囊泡中运输到高尔基体,在那里产生CTF?在轴突生长中发挥作用
和树枝状分支。我们进一步假设,在AD中,APP或CTF?积聚导致
旺盛和异常的海马轴突状发芽,最终导致树突状突起减少
神经元分支的复杂性和断裂。我们将研究km23-1-Rab6介导的APP的转运
和BACE1对高尔基体的影响,以及由此产生的APP片段对树突分支的影响。这个
结果将为在Golgi站点定向APP和BACE1的物理关联提供更有力的基础,以
减少BACE1活性和随后APP中间体的产生。Α更好地理解
Km23-1-Rab6调控高尔基体APP和BACE1相互作用的机制
树枝状分支应该有助于针对这一关键的贩运事件,以减少早期AD相关原因
事件。
我们对km23-1-Rab6复合体的结构建模揭示了蛋白质-
蛋白质相互作用。在目标1中,我们将研究蛋白质的定点突变对
Km23-1-Rab6复合体的时空调节以及对APP/BACE1结合和
车厢位置。重点将放在Soma Golgi和Golgi的APP和BACE1协会上
前哨(GO)开发树突,以便更好地了解APP背后的机制
在这些特定地区进行贩运、处理和发送信号。在目标2和目标3中,我们将使用Silico建模
并应用一种新的蛋白质涂抹技术来揭示km23-1与之相互作用的独特界面
Rab6在规范应用程序贩运和处理方面。精确的交互作用区域将用于设计
相应的多肽抑制剂对Km23-1-Rab6复合体形成的抑制作用
处理和AD相关的病理。而以前的大多数研究都使用了啮齿动物家族
AD(时尚)模型,这里我们将应用概括零星AD(SAD)的人类模型来测试我们的小说
Km23-1-Rab6抑制剂。利用这些关键相互作用蛋白质之间的隐藏接触区域作为
药物靶点将导致治疗模式的转变,克服过去治疗策略的局限性。
作为拟议研究的结果而开发的AD新治疗剂将是关键之一
下一代AD靶向疗法的成员。
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 }}
Lance Allen Liotta其他文献
Lance Allen Liotta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('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:














{{item.name}}会员




