Control of Heritable Protein Aggregation

该项目将研究生理变化如何调节酵母中基于蛋白质的遗传。基于蛋白质的可遗传元件（朊病毒），特别是在真菌中，是一种新的遗传元件，在其宿主细胞中产生可遗传的变化，而其基因的DNA没有任何变化。这种效应是通过蛋白质构象（称为同种型）之间的转换来实现的，其中一种（朊病毒同种型）能够通过诱导相同蛋白质的其他分子转换为相同的（朊病毒）同种型来复制自己。该项目专门研究这些转变如何得到另一类蛋白质的帮助，称为分子伴侣，其正常功能是促进蛋白质正确折叠并防止蛋白质错误折叠。了解蛋白质遗传的生理控制对酵母和其他真菌的工业应用具有潜在的影响。该研究与课程开发，教学和指导相结合，从而确保遗传学，生物化学和生物纳米技术领域的教育效益。研究团队包括男女研究生和本科生，并将故意保持一个多元化的团队。该项目还将通过促进格鲁吉亚理工学院跨学科中心的发展，帮助加强研究基础设施。本项目的主要目的是揭示蛋白质合成核糖体机制与遗传蛋白质聚集的细胞机制之间的联系。统一的假设是，核糖体相关的伴侣复合物作为生理变化的传感器，并介导这种变化对遗传蛋白质为基础的元素（朊病毒）的影响。这为生理和环境影响细胞和生物体的遗传结构提供了新的机制。该项目使用酵母作为模型系统，并采用遗传，生物化学和蛋白质组学技术的组合，包括新开发的聚合物检测方法，可能适用于酵母之外。

This project will investigate how physiological changes regulate protein-based inheritance in yeast. Protein-based heritable elements (prions), particularly in fungi, are novel genetic elements that produce heritable changes in their host cells without any change in the DNA of their genes. This effect is achieved by switching between protein conformations (termed isoforms) one of which (the prion isoform) is able to reproduce itself by inducing other molecules of the same protein to switch into the same (prion) isoform. This project looks specifically at how these transitions are aided by another class of proteins, termed molecular chaperones, whose normal function is to promote correct protein folding and prevent protein misfolding. Understanding the physiological control of protein-based inheritance has a potential impact on the industrial use of yeast and other fungi. The research is integrated with course development, teaching and mentoring, thus assuring educational benefits in the areas of genetics, biochemistry and bionanotechnology. The research team includes both men and women graduate and undergraduate students, and a diverse team will be deliberately maintained. This project will also help to strengthen research infrastructure by contributing to the development of interdisciplinary centers at Georgia Institute of Technology. The main objective of this project is to uncover the pathway connecting the protein synthesizing ribosomal machinery to the cellular apparatus of heritable protein aggregation. The unifying hypothesis is that the ribosome-associated chaperone complex serves as a sensor of physiological changes and mediates effects of such changes on heritable protein-based elements (prions). This provides a new mechanism for physiology and the environment to influence the hereditary constitution of the cell and organism. The project uses yeast as a model system and employs a combination of genetic, biochemical and proteomic techniques, including newly developed approaches for aggregate detection, potentially applicable beyond yeast.