Modelling yeast prion dynamics in the living cell

在过去的十年里，遗传完全基于DNA的教条受到了新的挑战。这部分是由于在酵母和其他真菌中发现了朊病毒。从历史上看，朊病毒已经被深入研究了它们引起疾病的能力，如“疯牛病”和人类形式的克雅氏病（CJD）。然而，在真菌中发现的朊病毒可能对宿主生物体有益，这表明朊病毒实际上可能代表了一种全新的蛋白质遗传形式。一个这样的朊病毒为基础的“表观遗传”决定因素在面包酵母（酿酒酵母）将在这个项目中进行研究;所谓的[PSI+]朊病毒。这种朊病毒可以显著改变酵母细胞对某些有毒化学物质的反应方式。我们计划采取的方法是一种新颖的方法，将生物实验与数学建模相结合，以研究朊病毒在活酵母细胞中的行为。这是我们首先在之前BBSRC资助的项目上开发的一种方法，这个新项目建立在此基础上，扩大了对朊病毒在不对称分裂的酵母细胞中复制过程的建模方法。我们的长期目标是完全了解朊病毒如何有效地产生并传递给其他酵母细胞的分子细节。我们已经知道，这需要细胞产生朊病毒“种子”，可以从母细胞传递到子细胞（我们称之为朊病毒传递的过程）。这些种子--我们称之为繁殖体--是通过分解在酵母细胞中发现的大得多的聚集形式的朊病毒蛋白而产生的。通过采用多学科的方法，我们的目标是建立机制，在不断增长的酵母细胞，以确保新的朊病毒种子有效地产生和传输到一个新的子细胞。该研究项目将建立在通过生物实验进行模型改进的迭代过程之上，以估计模型参数，然后评估出现的新模型的适当性。例如，这种方法将为我们提供评估和最终预测细胞组成或功能变化可能影响朊病毒复制和/或传播的方式的能力。其结果将是对这类重要的“表观遗传”元素-其中约20种现已被描述-如何在活细胞中复制以及如何干扰该过程的新理解。这一发现将指导未来对真菌和哺乳动物中这一过程的研究。这项研究的一个长期成果将是确定细胞中可以被新药靶向的成分，以阻止朊病毒种子的产生和/或传播。

The last decade has seen a new challenge to the dogma that inheritance is based exclusively on DNA. This has come in part from the discovery of prions in yeast and other fungi. Historically, prions have been intensively studied in relation to their ability to cause diseases such as 'Mad Cow Disease' and the human form, Creutzfeldt-Jakob Disease (CJD). However the discovery of prions in fungi that can potentially be of benefit to the host organism suggests that prions may actually represent an entirely new form of protein-based heredity. One such prion-based 'epigenetic' determinant in Baker's Yeast (Saccharomyces cerevisiae) will be studied in this project; the so-called [PSI+] prion. This prion can significantly alter the way that the yeast cell responds to certain toxic chemicals for example. The approach we are planning to take is a novel one, integrating biological experiments with mathematical modelling to study the behaviour of prions in a living yeast cell. This is an approach we first developed on a previous BBSRC-funded project and this new project builds on that, broadening the approach to model the process by which prions are replicated in an asymmetrically dividing yeast cell. Our long-term goal is to understand fully the molecular details of exactly how prions are so effectively generated and then passed on to other yeast cells. We already know that this requires cells to produce prion 'seeds' which can be passed from the mother cell to the daughter cell (a process we refer to as prion transmission). These seeds - which we refer to as propagons - are generated by breaking up much larger aggregated forms of the prion protein that are found in yeast cells. By employing a multidisciplinary approach we aim to establish the mechanism that operates in the growing yeast cell to ensure that new prion seeds are efficiently generated and transmitted to a new daughter cell. The research project will be built upon an iterative process of model improvement through biological experiments conducted to allow estimation of model parameters and then assessment of the adequacy of the new models that emerge. This approach will provide us, for example, with the ability to assess and ultimately predict the way in which changes in the cell's make up or function may impact on prion replication and/or transmission. The outcome will be a new understanding of how this important class of 'epigenetic' elements - some 20 of which have now been described - are replicated in the living cell, and how that process can be perturbed. The findings will guide future studies on the processes both in fungi and in mammals. A longer term outcome of the research will be identifying components of the cell that can be targeted by new drugs to block the generation and/or transmission of prion seeds.