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Environmental stress and heritable protein aggregation

环境压力和遗传性蛋白质聚集

基本信息

批准号：
1817976
负责人：
Yury Chernoff
金额：
$ 78.6万
依托单位：
Georgia Tech Research Corporation
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817976&HistoricalAwards=false
关键词：
Environmental stress heritable protein aggregation

项目摘要

The goal of this project is to decipher the relationship between environmental stress and protein-based inheritance. Protein-based heritable elements, best understood in yeast and other fungi, provide a new mechanism for inheritance and memory. Traits controlled by these elements are not directly encoded in DNA sequences. Instead, they depend on the presence of an altered (typically, aggregated) protein isoform (termed a prion), which can convert a normal cellular protein of the same amino acid sequence into a prion state. This work will investigate the role of stress in protein-based inheritance. The work could have broad significance for the industrial use of yeast, for example in production of alcohol and biofuels (processes associated with severe stresses). Additional outcomes will come from integration of the research with course development, teaching, and mentoring (including students from underrepresented groups), which will contribute to education in the areas of genetics, biochemistry and biotechnology. The project will also provide support for research infrastructure by strengthening the interdisciplinary centers and groups at Georgia Institute of Technology.Formation and propagation of yeast prions is modulated by other proteins (termed chaperones), that are normally involved in protein folding and defense against environmental stresses. This project investigates how stresses, such as heat shock, influence protein-based inheritance, what is the role of chaperones in these effects, and what is the impact of protein-based stress "memory" on stress resistance. The unifying hypothesis tested in this project is that prion-like aggregation could be adaptive due to generation of a subpopulation of cells, with a prion-based "memory" of stress, that are induced under stress conditions and possess increased resistance to subsequent stresses. Toxic prion aggregates may occur as by-products of such adaptive aggregation and are counteracted by the cellular stress defense machinery. Mechanisms of the effects of heat shock on prions and the role of intracellular relocation of chaperones in these effects will be investigated using a combination of genetic, cytological, biochemical and proteomic techniques.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个项目的目标是破译环境压力和蛋白质遗传之间的关系。以蛋白质为基础的遗传因子，在酵母和其他真菌中得到了最好的理解，提供了一种新的遗传和记忆机制。由这些元素控制的性状并不直接编码在DNA序列中。相反，它们依赖于一种改变的（通常是聚集的）蛋白质异构体（称为朊病毒）的存在，这种异构体可以将具有相同氨基酸序列的正常细胞蛋白转化为朊病毒状态。这项工作将探讨应激在蛋白质遗传中的作用。这项工作可能对酵母的工业应用具有广泛的意义，例如在酒精和生物燃料的生产中（与严重压力有关的过程）。将研究与课程开发、教学和指导（包括来自代表性不足群体的学生）相结合，将产生额外的成果，这将有助于遗传学、生物化学和生物技术领域的教育。该项目还将通过加强佐治亚理工学院的跨学科中心和小组，为研究基础设施提供支持。酵母朊病毒的形成和繁殖受到其他蛋白质（称为伴侣蛋白）的调节，这些蛋白质通常参与蛋白质折叠和抵御环境胁迫。本项目研究应激（如热休克）如何影响基于蛋白质的遗传，伴侣在这些影响中的作用，以及基于蛋白质的应激“记忆”对抗逆性的影响。在这个项目中测试的统一假设是，朊病毒样聚集可能是适应性的，因为产生了一个细胞亚群，具有基于朊病毒的压力“记忆”，在压力条件下诱导，对后续压力具有更强的抵抗力。毒性朊病毒聚集可能是这种适应性聚集的副产物，并被细胞应激防御机制所抵消。热休克对朊病毒的影响机制和伴侣在细胞内重新定位在这些影响中的作用将使用遗传学、细胞学、生化和蛋白质组学技术的组合进行研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling Amyloid Aggregation Kinetics: A Case Study with Sup35NM

淀粉样蛋白聚集动力学建模：Sup35NM 案例研究

DOI：
10.1021/acs.jpcb.0c11250
发表时间：
2021
期刊：
The Journal of Physical Chemistry B
影响因子：
0
作者：
Sharma, Aditi;McDonald, Matthew A.;Rose, Harrison B.;Chernoff, Yury O.;Behrens, Sven H.;Bommarius, Andreas S.
通讯作者：
Bommarius, Andreas S.

Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association