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Genetic Study of the Yeast Prion-Interacting Proteins

酵母朊病毒相互作用蛋白的遗传学研究

基本信息

批准号：
7990149
负责人：
YURY O CHERNOFF
金额：
$ 12.62万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-17 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990149
关键词：
Actins Address Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloidosis Autophagocytosis Bovine Spongiform Encephalopathy Budgets Cell division Cells Complex Cytoskeletal Proteins Cytoskeleton Data Disease Endocytic Vesicle Endocytosis Equilibrium Family Generations Genetic Golgi Apparatus Growth Health Human Huntington Disease Inclusion Bodies Individual Longevity Mammals Meat Mediating Micromanipulation Modeling Molecular Chaperones Monitor Neurodegenerative Disorders Parkinson Disease Pathway interactions Pattern Polymers Population Prion Diseases Prions Process Proliferating Protein Isoforms Proteins Public Health Research Research Personnel Role Solutions Structure System Testing Vacuole Work Yeasts age related base chronic wasting disease of elk and deer cytotoxicity design model development multicatalytic endopeptidase complex non-prion polyglutamine prion-based programs protein aggregate research study trafficking trait transmission process yeast prion

项目摘要

Prions are self-perpetuating protein isoforms that cause fatal neurodegenerative diseases in mammals and humans and control heritable traits in yeast. Most prions known to date form highly ordered fibrous polymers (amyloids), resembling aggregates involved in non-transmissible amyloidoses, such as Alzheimer's and Parkinson's diseases, or in polyglutamine disorders such as Huntington's disease. Mechanisms of clearance of the amyloid proteins are poorly understood. It is shown by us and other groups that prion propagation in yeast occurs via subsequent cycles of polymer fragmentation and growth, mediated by chaperone proteins. Accumulation of the large cytologically detectable aggregated structures (inclusion bodies) of prion proteins or other amyloidogenic proteins is observed in yeast in certain conditions and is sometimes associated with cytotoxicity. It is demonstrated by our data that some inclusion bodies interact with actin cytoskeletal networks, involved in endocytosis and trafficking of the endocytic vesicles to the vacuole. It is proposed that: 1) inclusion bodies represent intermediates in the prion generation or prion elimination pathways, and 2) prion propagation is regulated by a dynamic equilibrium between the actively proliferating prion units and inclusion bodies incapable of efficient propagation. Chaperones, proteolytic systems, cytoskeletal networks and trafficking pathways modulate prion propagation and clearance by shifting the equilibrium between inclusion bodies and proliferating prion units. Our proposal for the next budget period is designed to test specific predictions based on this general model. Specific aims of the project will specifically address the roles of chaperones, proteolytic pathways, cytoskeletal networks and intracellular trafficking pathways in generation and clearance of the prion protein aggregates. Taken together, the results of these experiments will uncover the mechanism of clearance of aggregated amyloidogenic proteins in yeast cells Relevance to public health: Mammalian prion diseases and many other amyloidoses are fatal and incurable. Mammalian prion diseases, such as "mad cow" disease and chronic wasting disease of elk and deer, represent a significant health threat due to a possibility of their transmission to humans with infected meat. Some amyloid diseases, such as Alzheimer's disease, are widespread and age-dependent, so that their importance is going to grow further in parallel with the eradication of other diseases and improvement of the average life span of human populations. This research will further establish yeast as a model for development of the strategies counteracting accumulation and propagation of prions and other toxic amyloids.

朊病毒是一种自我延续的蛋白质亚型，可导致哺乳动物致命的神经退行性疾病和人类，并控制酵母中的遗传特性。迄今为止已知的大多数朊病毒形成高度有序的纤维状聚合物（淀粉样蛋白），类似于非传染性淀粉样变性（如阿尔茨海默氏症）中涉及的聚集体和帕金森氏病，或多聚谷氨酰胺病症如亨廷顿氏病。机制对淀粉样蛋白的清除知之甚少。我们和其他研究小组表明，酵母中的朊病毒繁殖是通过随后的循环进行的分子伴侣蛋白介导的聚合物断裂和生长。细胞学上的大细胞聚集朊病毒蛋白或其他淀粉样蛋白的可检测的聚集结构（包涵体）是在某些条件下在酵母中观察到，有时与细胞毒性有关。这是由以下几点证明的：我们的数据表明，一些包涵体与肌动蛋白细胞骨架网络相互作用，参与内吞作用，内吞小泡向液泡的运输。本文认为：1）包涵体是朊病毒产生或消除过程中的中间产物途径，和2）朊病毒的传播是由一个动态平衡之间的积极增殖朊病毒单位和包涵体不能有效繁殖。伴侣蛋白，蛋白水解系统，细胞骨架网络和运输途径调节朊病毒的繁殖和清除，包涵体和增殖的朊病毒单位之间的平衡。我们对下一个预算期的建议是：旨在测试基于此通用模型的特定预测。该项目的具体目标将具体解决分子伴侣，蛋白水解途径，朊病毒蛋白产生和清除中的细胞骨架网络和细胞内运输途径集料.总之，这些实验的结果将揭示清除的机制，酵母细胞中聚集的淀粉样蛋白与公共卫生的相关性：哺乳动物朊病毒病和许多其他淀粉样变性是致命的，无法治愈哺乳动物朊病毒疾病，如“疯牛病”和麋鹿慢性消耗病，鹿是一个重大的健康威胁，因为它们有可能传播给受感染的人类。肉.一些淀粉样疾病，如阿尔茨海默病，是广泛的和年龄依赖性的，所以，在消灭其他疾病和改善卫生保健的同时，人类的平均寿命。这项研究将进一步建立酵母作为模型，发展对抗朊病毒和其他有毒物质的积累和繁殖的战略淀粉样蛋白

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Saccharomyces cerevisiae ESU1 gene, which is responsible for enhancement of termination suppression, corresponds to the 3'-terminal half of GAL11.

酿酒酵母 ESU1 基因负责增强终止抑制，对应于 GAL11 的 3 末端一半。

DOI：
10.1002/yea.1281
发表时间：
2005
期刊：
Yeast (Chichester, England)
影响因子：
0
作者：
Ono,Bun-ichiro;Futase,Tetsuro;Honda,Waka;Yoshida,Ryohma;Nakano,Kiyohiro;Yamamoto,Takayuki;Nakajima,Erina;Noskov,VladimirN;Negishi,Kazuo;Chen,Buxin;Chernoff,YuryO
通讯作者：
Chernoff,YuryO

Analysis of prion factors in yeast.

酵母中朊病毒因子的分析。