Amyloid elimination by Hsp104 and substrate-optimized variants

Hsp104 和底物优化变体消除淀粉样蛋白

基本信息

  • 批准号:
    7429951
  • 负责人:
  • 金额:
    $ 236.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-30 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

We are in dire need of innovations to combat several increasingly prevalent and inexorably lethal neurodegenerative disorders, including Alzheimer's and Parkinson's disease, which voraciously devour our social and economic resources. These disorders share a common pathogenic mechanism in which specific proteins misfold into a shared surprisingly generic conformation, termed amyloid. Amyloid fibers of diverse proteins adopt a similar `cross-β' structure, in which the strands of the β-sheets run perpendicular to the fiber axis. Further, highly cytotoxic oligomers possessing a distinct generic structure frequently accumulate prior to fibers. Although the specific protein that forms amyloid and precise localization of the deposits varies in each disease, these shared facets of amyloidogenesis bring hope that therapeutic strategies that target amyloid may have broad applications. The exceptional stability of amyloids, however, including: protease- and SDS-resistance, makes them extraordinarily difficult to clear. Indeed, they are widely perceived as intractable. Remarkably, we have found that a protein- remodeling factor from yeast, Hsp104, can rapidly disassemble amyloid fibers and oligomers comprised of the yeast prion proteins, Sup35 and Ure2. The unprecedented alacrity at which Hsp104 remodels these amyloid structures raises awareness that amyloid conformers are not intractable, and that a cellular factor capable of reversing amyloidogenesis has evolved. Curiously, although highly conserved in plants, bacteria and fungi, Hsp104 has been mysteriously lost from metazoan lineages. We hypothesize that application of Hsp104 to disease-associated amyloids may have broad therapeutic potential. Hence, we aim to: (1) annihilate amyloid fibers, oligomers and associated proteotoxicity of diverse human disease-associated proteins using Hsp104; (2) engineer or evolve substrate-optimized Hsp104 variants that attack select amyloidogenic proteins; and (3) generate Hsp104 or substrate-optimized variant therapies for animal models of amyloid-disorders. These studies will provide the foundations for new approaches to attack the devastating amyloid-disorders that plague humankind.
我们迫切需要创新,以打击越来越普遍的几个 不可避免的致命神经退行性疾病,包括阿尔茨海默氏症和帕金森氏症 疾病,广泛地吞噬了我们的社会和经济资源。这些疾病 共享一种常见的致病机制,其中特定的蛋白质折叠成共享 令人惊讶的是通用会议,称为淀粉样蛋白。多种蛋白质的淀粉样纤维 采用类似的“交叉β”结构,其中β-折叠的链垂直于 到纤维轴。此外,具有独特通用的高度细胞毒性低聚物 结构在纤维之前经常累积。虽然形成的特定蛋白质 沉积物的淀粉样蛋白和精确定位在每种疾病中都不同,这些共享 淀粉样生成的方面带来了靶向淀粉样蛋白的治疗策略的希望 有广泛的应用。然而,淀粉样蛋白的特殊稳定性包括: 蛋白酶和SDS抗性,使它们非常难以清除。确实,他们 被广泛认为是棘手的。值得注意的是,我们发现蛋白质 HSP104的酵母重塑因子可以迅速拆卸淀粉样纤维,并且 由酵母菌蛋白Sup35和Ure2组成的低聚物。前所未有的 HSP104重塑这些淀粉样结构的酸度提高了人们的意识 淀粉样蛋白构象异构体并不棘手,并且能够逆转的细胞因子 淀粉样生成已经发展。奇怪的是,尽管在植物中高度保守,但细菌 和真菌,HSP104神秘地从后生血统中丧失了。我们假设 将HSP104应用于疾病相关的淀粉样蛋白可能具有广泛的治疗 潜在的。因此,我们的目标是:(1)歼灭淀粉样纤维,低聚物和相关的 使用HSP104,潜水员与人类疾病相关的蛋白质的蛋白质毒性; (2)工程师 或进化攻击选择淀粉样蛋白的底物优化的HSP104变体; (3)生成HSP104或用于动物模型的底物优化变体疗法 淀粉样蛋白。这些研究将为新方法提供基础 攻击困扰人类的毁灭性淀粉样蛋白疾病。

项目成果

期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans.
  • DOI:
    10.1371/journal.pbio.1001346
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    9.8
  • 作者:
    Duennwald ML;Echeverria A;Shorter J
  • 通讯作者:
    Shorter J
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.
  • DOI:
    10.1016/j.brainres.2012.01.016
  • 发表时间:
    2012-06-26
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    King OD;Gitler AD;Shorter J
  • 通讯作者:
    Shorter J
The Surprising Role of Amyloid Fibrils in HIV Infection.
  • DOI:
    10.3390/biology1010058
  • 发表时间:
    2012-05-29
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Castellano LM;Shorter J
  • 通讯作者:
    Shorter J
Applying Hsp104 to protein-misfolding disorders.
Emergence and natural selection of drug-resistant prions.
  • DOI:
    10.1039/c004550k
  • 发表时间:
    2010-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shorter J
  • 通讯作者:
    Shorter J
{{ 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 }}

James Shorter其他文献

James Shorter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('James Shorter', 18)}}的其他基金

Engineering therapeutic TRIM11 disaggregases for Alzheimer's Disease-Related Dementias (ADRDs)
工程治疗 TRIM11 解聚酶治疗阿尔茨海默病相关痴呆症 (ADRD)
  • 批准号:
    10539674
  • 财政年份:
    2022
  • 资助金额:
    $ 236.25万
  • 项目类别:
Isolating small-molecule enhancers of HtrA1, an alpha-synuclein disaggregase
分离 HtrA1(一种 α-突触核蛋白解聚酶)的小分子增强子
  • 批准号:
    9374303
  • 财政年份:
    2017
  • 资助金额:
    $ 236.25万
  • 项目类别:
Exploring and enhancing Karyopherin beta-2 disaggregate activity
探索和增强核传递蛋白 beta-2 解聚活性
  • 批准号:
    9182306
  • 财政年份:
    2016
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining the mechanistic basis of a prion disaggregase
定义朊病毒解聚酶的机制基础
  • 批准号:
    8774612
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining mechanisms of AAA+ disaggregases
AAA 解聚的定义机制
  • 批准号:
    10155900
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining the mechanistic basis of a prion disaggregase
定义朊病毒解聚酶的机制基础
  • 批准号:
    8438661
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining the mechanistic basis of a prion disaggregase
定义朊病毒解聚酶的机制基础
  • 批准号:
    8974843
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining mechanisms of AAA+ disaggregases
AAA 解聚的定义机制
  • 批准号:
    10418627
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining the mechanistic basis of a prion disaggregase
定义朊病毒解聚酶的机制基础
  • 批准号:
    9239262
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:
Defining mechanisms of AAA+ disaggregases
AAA 解聚的定义机制
  • 批准号:
    10626853
  • 财政年份:
    2013
  • 资助金额:
    $ 236.25万
  • 项目类别:

相似国自然基金

CUEDC2调节SERCA2α活性参与心力衰竭发生和进展的机制研究
  • 批准号:
    81770248
  • 批准年份:
    2017
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
棉铃虫V-ATPase V1催化结构域基因的克隆与功能分析
  • 批准号:
    U1504318
  • 批准年份:
    2015
  • 资助金额:
    27.0 万元
  • 项目类别:
    联合基金项目

相似海外基金

+TIPs as novel host capsid-binding co-factors in early HIV-1 infection
TIP 作为早期 HIV-1 感染中新型宿主衣壳结合辅助因子
  • 批准号:
    10709142
  • 财政年份:
    2023
  • 资助金额:
    $ 236.25万
  • 项目类别:
Astrocytic regulation of energy balance on high-fat diet
星形胶质细胞对高脂饮食能量平衡的调节
  • 批准号:
    10734911
  • 财政年份:
    2023
  • 资助金额:
    $ 236.25万
  • 项目类别:
Elucidating the functional mechanism of NLRP3 inflammasome activation
阐明NLRP3炎症小体激活的功能机制
  • 批准号:
    10720435
  • 财政年份:
    2023
  • 资助金额:
    $ 236.25万
  • 项目类别:
Role of SPECC1L cytoskeletal protein in palate elevation dynamics
SPECC1L 细胞骨架蛋白在上颚抬高动态中的作用
  • 批准号:
    10638817
  • 财政年份:
    2023
  • 资助金额:
    $ 236.25万
  • 项目类别:
Therapeutic targeting of the SWI/SNF chromatin remodeler to regulate GBM chemosensitivity
SWI/SNF 染色质重塑剂的治疗靶向调节 GBM 化学敏感性
  • 批准号:
    10711581
  • 财政年份:
    2023
  • 资助金额:
    $ 236.25万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了