Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
基本信息
- 批准号:9978896
- 负责人:
- 金额:$ 39.38万
- 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:2018-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AmyloidCardiovascular DiseasesCellsCellular StressDiseaseEnsureGoalsHealthHumanLifeMass Spectrum AnalysisNeurodegenerative DisordersPlayProtein ConformationProteinsProteomeResearchRoleStressSubstrate SpecificitySystemTechniquesTechnologyTestingTherapeuticWorkYeastsconformerdisease phenotypehuman diseaseinsightmisfolded proteinnew technologynovel therapeuticspreventprogramsprotein foldingprotein misfoldingproteostasisrestoration
项目摘要
Abstract:
The proper folding of proteins is essential for all life, making aberrant protein folding severely problematic. The
protein homeostasis (proteostasis) network is a tightly regulated system that ensures that proteins are folded
and degraded as necessary. However, misfolded proteins can overwhelm the proteostasis network. Protein
misfolding is associated with numerous devastating neurodegenerative and cardiovascular disorders. Protein
disaggregases can engage misfolded substrates and unfold them, promoting their return to proper fold and
function. Disaggregases may serve as the final defense against collapse of the proteostasis network.
Disaggregases play key roles in maintaining cellular health, and can even regulate beneficial amyloids in
yeast. Amyloid is an exceptionally stable protein conformation that is implicated in numerous human diseases,
and amyloid is considered to be otherwise intractable. I hypothesize that disaggregases play key roles in
maintaining cellular health, but are vulnerable when the proteostasis network becomes overwhelmed in
disease. Therefore, technologies that modulate disaggregase activity might be therapeutically useful. However,
protein disaggregases are the least well characterized branch of the proteostasis network. I envision building a
research program focused on developing a more comprehensive understanding of how disaggregases counter
misfolding, both in health and under stress. I seek to elucidate how cells maintain proteostasis, how
proteostasis fails, and how protein disaggregases might ultimately be applied to prevent or even reverse
collapse of proteostasis. To further these goals, we will focus on three main themes over the next five years:
(1) we will develop and apply new technologies to study and modulate the substrate-specificity of Hsp104,
which regulates beneficial amyloid conformers in yeast. (2) We will characterize newly identified human
amyloid disaggregases to better understand their normal roles in maintaining cellular health and how they
might fail in disease. (3) We will apply new mass spectrometry techniques to study how protein-remodeling
factors select specific substrates to target and how this varies under stress conditions. Our work will elucidate
how disaggregases target specific substrates. Additionally, these finely-tuned disaggregases can be used as
probes to test the hypothesis that misfolded species are toxic, and that restoration of proteins to their native
folds and functions can reverse disease phenotypes. Ultimately we aim to apply the findings from these studies
to develop new strategies to treat neurodegenerative disease. This is especially important because, despite
intense efforts, there are no therapeutics available to treat protein-misfolding disorders.
摘要:
蛋白质的正确折叠对所有生命都是必不可少的,这使得异常的蛋白质折叠成为严重的问题。这个
蛋白质稳态网络是一个严密的调节系统,确保蛋白质折叠
并在必要时降级。然而,错误折叠的蛋白质可能会压倒蛋白质平衡网络。蛋白
错误折叠与许多毁灭性的神经退行性疾病和心血管疾病有关。蛋白
解聚酶可以结合错误折叠的底物并将其解开,促进其恢复正常折叠和
功能。解聚酶可能是防止蛋白质平衡网络崩溃的最后防御措施。
解聚酶在维持细胞健康方面起着关键作用,甚至可以调节有益的淀粉样蛋白
酵母。淀粉样蛋白是一种非常稳定的蛋白质构象,与许多人类疾病有关,
而淀粉样蛋白在其他方面被认为是难以治愈的。我假设解聚体在
维持细胞健康,但当蛋白质平衡网络变得不堪重负时,
疾病。因此,调节解聚酶活性的技术可能在治疗上有用。然而,
蛋白质解聚酶是蛋白质平衡网络中特征最差的分支。我设想建造一座
研究计划的重点是更全面地了解解聚是如何对抗的
无论是在健康方面还是在压力下,都会出现折叠错误。我试图阐明细胞如何维持蛋白质平衡,如何
蛋白质平衡失败,以及蛋白质解聚酶最终如何应用于预防甚至逆转
蛋白质平衡的崩溃。为了实现这些目标,我们将在未来五年重点关注三个主题:
(1)我们将开发和应用新技术来研究和调节Hsp104的底物特异性,
它调节酵母中有益的淀粉样物构象。(2)我们将描述新发现的人类
淀粉样蛋白解聚以更好地了解它们在维持细胞健康中的正常作用以及它们是如何
可能会在疾病中失败。(3)我们将应用新的质谱学技术来研究蛋白质重塑
因素选择特定的底物作为目标,以及在压力条件下这一点如何变化。我们的工作将阐明
解聚酶如何针对特定的底物。此外,这些经过精细调整的解聚体还可以用作
测试错误折叠的物种是有毒的,以及蛋白质恢复到原始状态的假设的探测器
折叠和功能可以逆转疾病的表型。最终,我们的目标是应用这些研究的结果
开发治疗神经退行性疾病的新策略。这一点特别重要,因为尽管
在激烈的努力下,还没有治疗蛋白质错误折叠障碍的疗法。
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)
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Meredith E. Jackrel其他文献
Histidine-rich enantiomeric peptide coacervates enhance antigen sequestration and presentation to T cells
富含组氨酸的对映体肽凝聚物增强抗原隔离和呈递给 T 细胞
- DOI:
10.1039/d5sc01163a - 发表时间:
2025-03-20 - 期刊:
- 影响因子:7.400
- 作者:
Ushasi Pramanik;Anirban Das;Elise M. Brown;Heather L. Struckman;Huihao Wang;Samuel Stealey;Macy L. Sprunger;Abdul Wasim;Jonathan Fascetti;Jagannath Mondal;Jonathan R. Silva;Silviya P. Zustiak;Meredith E. Jackrel;Jai S. Rudra - 通讯作者:
Jai S. Rudra
Structure of Calcarisporie lla thermophila Hsp 104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events Highlights
拮抗多种蛋白毒性错误折叠事件的嗜热钙孢菌 Hsp 104 解聚酶的结构
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
K. Michalska;Kaiming Zhang;Z. March;C. Hatzos;G. Pintilie;LanceBigelow;L. Castellano;Leann Miles;Meredith E. Jackrel;E. Chuang;R. Jedrzejczak;J. Shorter;W. Chiu;A. Joachimiak - 通讯作者:
A. Joachimiak
Tuning Hsp104 specificity to selectively detoxify a -synuclein
调节 Hsp104 特异性以选择性解毒 a-突触核蛋白
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Korrie L. Mack;Hanna Kim;Edward M Barbieri;Kimberlee A. Caldwell;G. Caldwell;J. Shorter;JiaBei Lin;Sylvanne Braganza;Meredith E. Jackrel;J. Denizio;Xiaohui Yan;E. Chuang;Amber Tariq;Ryan R. Cupo;L. Castellano - 通讯作者:
L. Castellano
Potentiated Hsp104 Variants Antagonize Diverse Protein Misfolding Events
- DOI:
10.1016/j.bpj.2012.11.3167 - 发表时间:
2013-01-29 - 期刊:
- 影响因子:
- 作者:
Meredith E. Jackrel;Morgan E. DeSantis;Laura M. Castellano;James Shorter - 通讯作者:
James Shorter
Probing the drivers of emStaphylococcus aureus/em biofilm protein amyloidogenesis and disrupting biofilms with engineered protein disaggregases
探究金黄色葡萄球菌生物膜蛋白淀粉样蛋白生成的驱动因素,并利用工程化蛋白解聚酶破坏生物膜
- DOI:
10.1128/mbio.00587-23 - 发表时间:
2023-06-13 - 期刊:
- 影响因子:4.700
- 作者:
Matthew K. Howard;Karlie R. Miller;Brian S. Sohn;Jeremy J. Ryan;Andy Xu;Meredith E. Jackrel;Matthew Parsek - 通讯作者:
Matthew Parsek
Meredith E. Jackrel的其他文献
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{{ truncateString('Meredith E. Jackrel', 18)}}的其他基金
Delineating the role of Matrin-3 in driving aberrant liquid-liquid phase separation that underpins ALS/FTD
描述 Matrin-3 在驱动支撑 ALS/FTD 的异常液-液相分离中的作用
- 批准号:
10581838 - 财政年份:2023
- 资助金额:
$ 39.38万 - 项目类别:
Amyloid-inspired Vaccine Delivery for the Elderly
为老年人提供淀粉样蛋白疫苗
- 批准号:
10300848 - 财政年份:2021
- 资助金额:
$ 39.38万 - 项目类别:
Amyloid-inspired Vaccine Delivery for the Elderly
为老年人提供淀粉样蛋白疫苗
- 批准号:
10457013 - 财政年份:2021
- 资助金额:
$ 39.38万 - 项目类别:
Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
- 批准号:
10457746 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
- 批准号:
9752606 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
- 批准号:
10217191 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
- 批准号:
10460941 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Safeguards of the Proteome: Elucidating the Roles of Protein Disaggregases
蛋白质组的保障:阐明蛋白质解聚酶的作用
- 批准号:
10283362 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
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