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Quantitative approaches to defining normal and aberrant protein homeostasis

定义正常和异常蛋白质稳态的定量方法

基本信息

批准号：
BB/H003843/1
负责人：
Christopher Dobson
金额：
$ 251.7万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2010
资助国家：
英国
起止时间：
2010 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH003843%2F1
关键词：
Quantitative approaches defining normal aberrant

项目摘要

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.

所有生命系统的运作能力都需要对蛋白质的行为进行高度的调控，蛋白质分子基本上参与了它们内部发生的所有生化反应。蛋白质通常通过采用特定的构象来执行其功能，这些构象被称为天然状态，这些状态在其氨基酸序列中编码。因此，分子生物学中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，蛋白质的非自然状态也在决定细胞活动的正常发展中发挥着重要作用。各种疾病，包括全身性疾病，如II型糖尿病和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，帕金森病和各种普里恩疾病，已被发现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，我们付出了大量的努力，包括我们自己的研究小组所做的大量工作，通过提高我们了解蛋白质行为的能力，包括折叠、错误折叠和组装，来解决这些问题。我们在本申请中提出的方法基于两个实现。首先，对蛋白质动态平衡的研究为全面描述蛋白质在细胞中的行为提供了一个总体框架。第二，现在可以通过利用纳米科学、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来取得重大进展。因此，我们聚集了来自这些学科的研究人员，这些研究人员已经建立了成功合作的记录，以提出一个雄心勃勃的计划或研究，目的是提高我们能够理性和定量地了解细胞过程的结果的水平。更具体地说，我们建议在化学系(Dobson教授和Vendruscolo博士)进行研究，通过实验和理论相结合的方式，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、淀粉样纤维及其相互转化的途径。纳米科学中心(Welland教授)的活动将致力于利用纳米科学技术在蛋白质行为的不同方面建立定量关系，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(克劳瑟博士)和医学系(洛马斯教授)，我们将使用体内果蝇模型结合理论预测来加强我们对错误折叠疾病的物理化学起源的理解，并探索合理的治疗策略。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accurate determination of interstrand distances and alignment in amyloid fibrils by magic angle spinning NMR.

DOI：
10.1021/jp106675h
发表时间：
2010-10-28
期刊：
JOURNAL OF PHYSICAL CHEMISTRY B
影响因子：
3.3
作者：
Caporini, Marc A.;Bajaj, Vikram S.;Veshtort, Mikhail;Fitzpatrick, Anthony;MacPhee, Cait E.;Vendruscolo, Michele;Dobson, Christopher M.;Griffin, Robert G.
通讯作者：
Griffin, Robert G.

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