Elucidating mechanisms of amyloid nucleation in vivo
阐明体内淀粉样成核机制
基本信息
- 批准号:10531912
- 负责人:
- 金额:$ 31.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAdsorptionAgeAgingAlzheimer&aposs DiseaseAmyloidBiochemicalBiophysicsCellsCellular biologyCytologyDataDependenceDiseaseDisparateEventFlow CytometryFluorescence Resonance Energy TransferGenetic PolymorphismGoalsGrantInvestigationKineticsLaboratoriesLongevityMemoryMolecularMolecular ConformationMutationNatureNerve DegenerationNeurodegenerative DisordersOrganismOutcomePathologicPathologic ProcessesPhasePhysical condensationPhysiologicalPhysiological ProcessesPolymersPolymorphPopulationProbabilityProteinsResearchRoleSignal TransductionSolubilitySpecificityStructureTestingTherapeuticThermodynamicsTimeamyloid formationamyloid structureanalytical tooldensityenvironmental changeexperimental studyfluorophorein vivoinsightnovel therapeuticspolypeptideprotein functionproteostasisscreeningstress granuletool
项目摘要
Project Summary
Amyloids exert numerous physiological and pathological activities. On the one hand, they perpetuate molecular
memories and transduce intracellular signals; on the other, they precipitate incurable neurodegenerative and
age-associated diseases. These disparate activities unfold over time scales that exceed the lifespan of the
proteins or even the cells that harbor them. Our long-term goal is to determine whether, and how, these time
scales emerge from the kinetics of amyloid formation in living cells. Toward this goal, we have focused on the
critical first step of amyloid formation: nucleation. The probabilistic nature of nucleation has made its study
exceedingly difficult with established cytological tools. We therefore developed Distributed Amphifluoric FRET
(DAmFRET) to quantify nucleation as a function of a given protein’s concentration in living cells. We have now
used DAmFRET to analyze nucleation of diverse amyloids and related polymers, and these data lead us to
propose the central hypothesis of this grant: low-specificity interactions critically influence the rates and
structural outcomes of amyloid nucleation in vivo. This hypothesis makes the following predictions that will be
tested in our Specific Aims: that nucleation will favor increasingly labile amyloids with 1) increasing protein
concentration or 2) condensation of the protein; and 3) that the ability of amyloids of one protein to nucleate
amyloids of a different protein depends on their disordered content rather than their structure. Completing this
investigation will reveal critical mechanistic features of nucleation by diverse proteins in living cells, including
the thermodynamic underpinnings of nucleation barriers, and networks of pathological cross-seeding. It will also
have opened a conduit to fundamental physical insights that are presently beyond the reach of cell biology.
These will yield a deeper understanding of, and ultimately new therapeutic options for, age- associated and
neurodegenerative diseases.
项目摘要
淀粉样蛋白具有多种生理和病理活性。一方面,它们使分子
记忆和细胞内信号;另一方面,他们沉淀不可治愈的神经退行性疾病,
与年龄相关的疾病。这些不同的活动随着时间的推移而展开,
蛋白质甚至是携带它们的细胞。我们的长期目标是确定这些时间是否以及如何
鳞片是由活细胞中淀粉样蛋白形成的动力学产生的。为了实现这一目标,我们把重点放在
淀粉样蛋白形成的关键第一步:成核。成核的概率性质使它的研究
用现有的细胞学工具非常困难。因此,我们开发了分布式Amphiphibrium FRET
(DAmFRET)来量化成核作用作为活细胞中给定蛋白质浓度的函数。我们现在已经
使用DAmFRET分析不同淀粉样蛋白和相关聚合物的成核,这些数据使我们
我提出了这个补助金的中心假设:低特异性相互作用严重影响了利率,
体内淀粉样蛋白成核的结构结果。这一假设做出了以下预测,
在我们的特定目标中测试:随着1)蛋白质含量的增加,成核作用将有利于越来越不稳定的淀粉样蛋白
浓缩或2)蛋白质的缩合;和3)一种蛋白质的淀粉样蛋白成核的能力
不同蛋白质的淀粉样蛋白取决于它们的无序含量而不是它们的结构。完成本
研究将揭示活细胞中不同蛋白质成核的关键机制特征,包括
成核障碍的热力学基础和病理交叉播种的网络。它还将
已经打开了一个管道,基本的物理见解,目前超出了细胞生物学的范围。
这些将产生更深入的理解,并最终新的治疗选择,年龄相关,
神经退行性疾病
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal.
- DOI:10.7554/elife.86939
- 发表时间:2023-11-03
- 期刊:
- 影响因子:7.7
- 作者:Kandola T;Venkatesan S;Zhang J;Lerbakken BT;Von Schulze A;Blanck JF;Wu J;Unruh JR;Berry P;Lange JJ;Box AC;Cook M;Sagui C;Halfmann R
- 通讯作者:Halfmann R
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Randal Arthur Halfmann其他文献
Randal Arthur Halfmann的其他文献
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{{ truncateString('Randal Arthur Halfmann', 18)}}的其他基金
Multilineage DAmFRET to investigate AD/ADRD protein phase behavior in neural tissue models
多谱系 DAmFRET 研究神经组织模型中 AD/ADRD 蛋白相行为
- 批准号:
10583428 - 财政年份:2023
- 资助金额:
$ 31.76万 - 项目类别:
Elucidating mechanisms of amyloid nucleation in vivo
阐明体内淀粉样成核机制
- 批准号:
10320915 - 财政年份:2020
- 资助金额:
$ 31.76万 - 项目类别:
Elucidating mechanisms of amyloid nucleation in vivo
阐明体内淀粉样成核机制
- 批准号:
9886371 - 财政年份:2020
- 资助金额:
$ 31.76万 - 项目类别:
Contributions of protein aggregation to gene regulation and phenotypic diversity
蛋白质聚集对基因调控和表型多样性的贡献
- 批准号:
9104516 - 财政年份:2015
- 资助金额:
$ 31.76万 - 项目类别:
Contributions of protein aggregation to gene regulation and phenotypic diversity
蛋白质聚集对基因调控和表型多样性的贡献
- 批准号:
8335441 - 财政年份:2011
- 资助金额:
$ 31.76万 - 项目类别:
Contributions of protein aggregation to gene regulation and phenotypic diversity
蛋白质聚集对基因调控和表型多样性的贡献
- 批准号:
8537226 - 财政年份:2011
- 资助金额:
$ 31.76万 - 项目类别:
Contributions of protein aggregation to gene regulation and phenotypic diversity
蛋白质聚集对基因调控和表型多样性的贡献
- 批准号:
8213104 - 财政年份:2011
- 资助金额:
$ 31.76万 - 项目类别:
Contributions of protein aggregation to gene regulation and phenotypic diversity
蛋白质聚集对基因调控和表型多样性的贡献
- 批准号:
8734278 - 财政年份:2011
- 资助金额:
$ 31.76万 - 项目类别:
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