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

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

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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:
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