Generation of heritable protein aggregates

这个项目的目标是了解真核细胞中可遗传的蛋白质聚集体是如何形成的。酵母和其他真菌中的可遗传聚集蛋白组件，称为真菌蛋白，为遗传和记忆提供了一种新的机制，因为它们控制着不直接在DNA序列中编码的可遗传特征，但以重排蛋白质的形式在世代之间传递。这个项目将研究可遗传的聚集体最初是如何从非聚集蛋白质中产生的。了解可遗传聚集体的形成对于将环境和生理过程(如细胞应激)与细胞和生物体的可遗传特性联系起来非常重要。这也可能有助于改善工业应用，例如利用酵母生产酒精和生物燃料。研究项目将与课程开发、教学和指导相结合，从而促进在遗传学、生物化学和生物技术领域的不同劳动力的教育。它将通过加强跨学科互动为研究基础设施提供额外的支持。本项目检验的统一假说是，在体内形成可遗传聚集体的能力受到易于聚集的蛋白质、细胞因子和环境之间复杂相互作用的调节，并处于最小化不受控制的聚集的进化压力下。这一假设将在拟议的实验中得到检验。将揭示将环境压力与可遗传蛋白质聚集联系起来的途径。强调一些蛋白质聚集体促进其他蛋白质聚集的能力的机制将被研究。在进化中蛋白质聚集能力的差异将被解决。通过液-液相分离形成的可逆蛋白质凝聚体和不可逆蛋白质聚集体之间的关系将被破译。使蛋白质聚集体可遗传的分子特征的出现将被研究。将探索新生成的聚集体与压力诱导的蛋白质折叠助手(称为伴侣)之间的相互作用。该项目将结合遗传学、细胞学、生化和生物物理技术。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The goal of this project is to understand how heritable protein aggregates form in a eukaryotic cell. Heritable aggregated protein assemblies in yeast and other fungi, known as fungal prions, provide a new mechanism for the inheritance and memory, as they control heritable traits that are not directly encoded in DNA sequence but are passed between generations in the form of rearranged proteins. This project will investigate how heritable aggregates are initially generated from a non-aggregated protein. Understanding the formation of heritable aggregates is important for linking environmental and physiological processes, such as cell stress, to heritable properties of cells and organisms. This may also help improve industrial applications, such as production of alcohol and biofuels by yeast. Research project will be integrated with course development, teaching and mentoring, thus contributing to education of diverse workforce in the areas of genetics, biochemistry and biotechnology. It will provide additional support for research infrastructure by strengthening interdisciplinary interactions. The unifying hypothesis tested in this project is that the ability to form a heritable aggregate in vivo is modulated by complex interactions between aggregation-prone proteins, cellular factors and environment, and is under the evolutionary pressure that is minimizing uncontrolled aggregation. This hypothesis will be tested in proposed experiments. Pathways linking environmental stress to heritable protein aggregation will be uncovered. Mechanisms underlining the abilities of some protein aggregates to promote aggregation of other proteins will be studied. Divergence of protein aggregation capabilities in evolution will be addressed. Relationships between reversible protein condensates, formed by liquid-liquid phase separation, and irreversible protein aggregates will be deciphered. Emergence of molecular features that make protein aggregates heritable will be investigated. Interactions of newly generated aggregates with stress-induced protein folding helpers, termed chaperones, will be explored. The project will employ a combination of genetic, cytological, biochemical and biophysical 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.