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Protein Aggregation and Inclusion Body Formation

蛋白质聚集和包涵体形成

基本信息

批准号：
9098811
负责人：
RON R KOPITO
金额：
$ 58.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098811
关键词：
26S proteasome Aging Biological Biological Assay Biology Biosensor Caenorhabditis elegans Cell Survival Cell model Cells Chickens Chronic Cytoplasmic Inclusion Data Deposition Development Diagnostic Disease Environment Epidemic Equilibrium Event Fluorescence Funding Genetic Models Heat shock proteins Human Huntington Disease Huntington gene Impairment Inclusion Bodies Individual Kinetics Lead Mammalian Cell Maps Measurement Methodology Modeling Molecular Monitor Mutation Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathology Polyubiquitination Population Process Protein Biosynthesis Proteins Proteome Proteomics Publishing Recruitment Activity Reporting Research Research Project Grants Research Support Role Structure Surface System Technology Temperature Testing Time Tissues Ubiquitin Work base bioimaging brain cell egg flexibility in vivo insight loss of function multicatalytic endopeptidase complex mutant new therapeutic target polyglutamine population based protein aggregate protein aggregation protein degradation protein folding response single cell analysis stress protein stressor targeted treatment therapeutic biomarker

项目摘要

DESCRIPTION (provided by applicant): Accumulation of protein aggregates and ubiquitin (Ub) into cytoplasmic inclusion bodies (IB) is the single most definitive diagnostic neuropathological marker of neurodegenerative disease. Despite this universal diagnostic significance, the cell biological mechanisms underlying IB formation and, indeed, whether formation of these structures reflects a pathogenic or protective process, remains an unresolved mystery. The long-term objective of this research project is to elucidate the molecular mechanisms that underlie IB formation and Ub deposition and to develop an integrated understanding of how mammalian cells respond to the chronic expression of pathogenic, aggregation-prone proteins. The research supported by this project during the previous funding period exploited single-cell analysis of a cellular model of Huntington's disease (HD) to show that, although mature IB contain both aggregated huntingtin (htt) and Ub, the two proteins are recruited to IB with vastly different kinetics. These observations, together with emerging data from genetic models of neurodegenerative disease, suggest a model in which chronic expression of a folding-defective aggregation-prone protein like htt, burdens the cell's proteostasis capacity (ie, the cell's ability to maintain the correct dynamic equilibrium between protein folding and degradation) leading to a progressive diversion of normal proteins from productive folding to the ubiquitin proteasome system, ultimately overwhelming the cell's capacity to degrade proteins. The research in this proposal aims to rigorously testand refine this emerging model using state-of-the-art proteomic and bioimaging technologies. These studies will provide a comprehensive understanding of the dynamic interaction between protein aggregation and proteostasis and will illuminate one of the longest-standing controversies in neurodegenerative disease biology.

描述（由申请方提供）：蛋白质聚集体和泛素（Ub）在胞质包涵体（IB）中的蓄积是神经退行性疾病的唯一最明确的诊断性神经病理学标志物。尽管具有普遍的诊断意义，但IB形成的细胞生物学机制，以及这些结构的形成是否反映了致病或保护过程，仍然是一个未解之谜。该研究项目的长期目标是阐明IB形成和Ub沉积的分子机制，并对哺乳动物细胞如何应对致病性、易聚集蛋白的慢性表达形成综合理解。该项目在上一个资助期内支持的研究利用了亨廷顿病（HD）细胞模型的单细胞分析，表明尽管成熟的IB含有聚集的亨廷顿蛋白（htt）和Ub，但这两种蛋白质以截然不同的动力学被招募到IB中。这些观察结果以及来自神经退行性疾病遗传模型的新数据表明，在一种模型中，htt等折叠缺陷、易于聚集的蛋白质的慢性表达会给细胞的蛋白质稳态能力带来负担（即细胞维持蛋白质折叠和降解之间正确动态平衡的能力）导致正常蛋白质从生产性折叠逐渐转向泛素蛋白酶体系统，最终使细胞无法降解蛋白质。该提案中的研究旨在使用最先进的蛋白质组学和生物成像技术严格测试和完善这一新兴模型。这些研究将全面了解蛋白质聚集和蛋白质稳态之间的动态相互作用，并将阐明神经退行性疾病生物学中存在时间最长的争议之一。

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（0）

Altered testicular gene expression patterns in mice lacking the polyubiquitin gene Ubb.

DOI：
10.1002/mrd.21318
发表时间：
2011-06
期刊：
MOLECULAR REPRODUCTION AND DEVELOPMENT
影响因子：
2.5
作者：
Sinnar, Shamim A.;Small, Christopher L.;Evanoff, Ryan M.;Reinholdt, Laura G.;Griswold, Michael D.;Kopito, Ron R.;Ryu, Kwon-Yul
通讯作者：
Ryu, Kwon-Yul

Prion-Like Characteristics of Polyglutamine-Containing Proteins.

DOI：
10.1101/cshperspect.a024257
发表时间：
2018-02-01
期刊：
Cold Spring Harbor perspectives in medicine
影响因子：
5.4
作者：
Pearce MMP;Kopito RR
通讯作者：
Kopito RR

Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease.

DOI：
10.1083/jcb.201110093
发表时间：
2012-03-05
期刊：
The Journal of cell biology
影响因子：
0
作者：
Hipp MS;Patel CN;Bersuker K;Riley BE;Kaiser SE;Shaler TA;Brandeis M;Kopito RR
通讯作者：
Kopito RR

Fibrillar structure and charge determine the interaction of polyglutamine protein aggregates with the cell surface.

纤维结构和电荷决定了聚谷氨酰胺蛋白聚集体与细胞表面的相互作用。

DOI：
10.1074/jbc.m112.372474
发表时间：
2012
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Trevino,RSean;Lauckner,JaneE;Sourigues,Yannick;Pearce,MargaretM;Bousset,Luc;Melki,Ronald;Kopito,RonR
通讯作者：
Kopito,RonR

The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease.