Quantitative approaches to defining normal and aberrant protein homeostasis

所有生命系统的功能都需要对蛋白质的行为进行高水平的调节，蛋白质是一种分子，基本上参与了发生在它们体内的所有生化反应。蛋白质通常通过采用特定的构象来实现它们的功能，这些构象被称为天然状态，编码在它们的氨基酸序列中。因此，分子生物学的许多研究都集中在蛋白质天然状态的性质上。然而，越来越明显的是，蛋白质的非天然状态在决定细胞活动的正常发展中也起着重要作用。各种疾病，包括全身性疾病，如2型糖尿病和与透析相关的淀粉样变性，以及神经退行性疾病，如阿尔茨海默氏症、帕金森病和各种朊病毒疾病，已被确定与蛋白质的错误折叠及其随后的聚集有关。在过去的几年里，包括我们自己的研究小组的大量工作在内，我们付出了相当大的努力，通过提高我们对蛋白质行为的理解能力来解决这些问题，包括折叠、错误折叠和组装。我们在此应用程序中提出的方法基于两个实现。首先，对蛋白质稳态的研究提供了一个总体框架，以形成对细胞中蛋白质行为的全面描述。其次，利用纳米科学、化学和神经生物学等学科的技术和概念发展所提供的机会，现在可以取得重大进展。因此，我们汇集了来自这些学科的研究人员，他们已经建立了成功合作的记录，提出了一个雄心勃勃的计划或研究，目标是提高我们能够理性和定量地理解细胞过程结果的水平。更具体地说，我们建议在化学系（Dobson教授和Vendruscolo博士）开展研究，通过实验和理论的结合，详细确定蛋白质的多种可能状态，包括部分折叠的构象，错误折叠的中间产物，淀粉样原纤维，以及它们相互转化的途径。纳米科学中心（Welland教授）的活动将致力于利用纳米科学技术建立蛋白质行为不同方面之间的定量关系，包括它们的聚集率和淀粉样蛋白结构的机械特性。最后，在遗传学系（Crowther博士）和医学系（Lomas教授），我们将使用体内果蝇模型与理论预测相结合，以增强我们对错误折叠疾病的物理化学起源的理解，并探索合理治疗策略的发展。

The ability of all living systems to function requires a high level of regulation of the behaviour of proteins, which are the molecules that are involved in essentially all the biochemical reactions taking place within them. Proteins usually carry out their functions by adopting specific conformations, known as native states, which are encoded in their amino acid sequences. Much research in molecular biology has therefore been focused on the properties of native states of proteins. It is increasingly evident, however, that non-native states of proteins also play a fundamental role in determining the normal development of cellular activities. A variety of diseases, which include systemic conditions such as type II diabetes and dialysis-related amyloidosis, and neurodegenerative conditions such as Alzheimer's, Parkinson's and the various prion diseases, have been identified that are associated with the incorrect folding of proteins and their subsequent aggregation. Very considerable efforts, including much work by our own research groups, have been devoted in the last several years to addressing these problems by enhancing our ability of understanding the behaviour of proteins, including folding, misfolding and assembly. The approach that we propose in this application is based on two realisations. The first is that the investigation of protein homeostasis provides a general framework to formulate a comprehensive description of the behaviour of proteins in the cell. The second is that major advances can now be made by exploiting the opportunities offered by technical and conceptual developments that have taken place in disciplines such nanoscience, chemistry and neurobiology. We have thus brought together researchers from these disciplines that have already an established track record of successful collaborations to put forward an ambitious programme or research with the goal of increasing the level at which we can understand rationally and quantitatively the outcome of cellular processes. More specifically, we propose to carry out research at the Department of Chemistry (Prof Dobson and Dr Vendruscolo) to achieve a detailed determination, by a combination of experiment and theory, of the multiple possible states of proteins, including partially folded conformations, misfolding intermediates, amyloid fibrils, as well as of the pathways of their interconversion. The activity at the Nanoscience Centre (Prof Welland) will be devoted to the use of nanoscience techniques to establish quantitative relationships between different aspects of protein behaviour, including their aggregation rates and the mechanical properties of amyloid structures. Finally, at the Departments of Genetics (Dr. Crowther) and of Medicine (Prof Lomas) we will use in vivo Drosophila models in conjunction with theoretical predictions to enhance our understanding of the physico-chemical origin of misfolding diseases and to explore the development of rational strategies for their treatment.