Environmental stress and heritable protein aggregation

该项目的目标是破译环境压力和基于蛋白质的遗传之间的关系。基于蛋白质的遗传元件，在酵母和其他真菌中得到了最好的理解，为遗传和记忆提供了一种新的机制。由这些元件控制的性状不直接编码在DNA序列中。相反，它们依赖于一种改变的（通常是聚集的）蛋白质同种型（称为朊病毒）的存在，这种蛋白质同种型可以将具有相同氨基酸序列的正常细胞蛋白质转化为朊病毒状态。这项工作将研究压力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（与严重压力相关的过程）中。其他成果将来自研究与课程开发，教学和指导（包括来自代表性不足群体的学生）的整合，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格鲁吉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其他蛋白质（称为分子伴侣）的调节，这些蛋白质通常参与蛋白质折叠和对环境压力的防御。该项目研究了压力，如热休克，如何影响蛋白质遗传，伴侣在这些影响中的作用是什么，以及蛋白质压力“记忆”对抗压力的影响是什么。 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，由于产生了一个亚群的细胞，与朊病毒为基础的“记忆”的压力，这是诱导压力条件下，并具有增加的阻力，随后的压力。毒性朊病毒聚集体可能作为这种适应性聚集的副产物出现，并被细胞应激防御机制抵消。热休克对朊病毒的影响机制和分子伴侣在这些影响中的细胞内迁移作用将使用遗传学、细胞学、生物化学和蛋白质组学技术相结合进行研究。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.