Defining and exploiting the role of PML protein in innate immune responses to pathogens

定义和利用 PML 蛋白在病原体先天免疫反应中的作用

• 批准号: MR/P022901/1
• 负责人: Keith Leppard
• 金额: $ 54.86万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022901%2F1
• 关键词: Defining; exploiting; role; PML; protein

Just as we swap our lightweight summer clothes for winter ones when it gets cold, so our cells need to make different proteins to meet changing circumstances, such as when they are invaded by a virus. This project is about understanding how our cells change in response to virus infection, in particular, how they make what is termed an innate immune response. This response involves the cell making new proteins that act to limit the growth and spread of the virus. Proteins are produced from instructions carried in RNA molecules. These in turn are made by copying the information held in the cell's genes, a process known as transcription. So, when a cell is stressed by a virus infection, it responds by changes in its pattern of gene transcription. We have discovered that a protein known as PML-II behaves like a master regulator of genes whose transcription is turned on rapidly after a virus infection. A major aim of this project is to find out just how broad is the set of genes that responds to the presence of this protein and, most importantly, what distinguishes these genes from those that are independent of it. We plan to use the most modern techniques to examine events across all the 20,000 or more genes in the human genome when an innate immune response is launched. In this way, we will get a system-wide view of the effects of the PML-II protein that is not limited by any preconceptions.Going on from this, we intend to find out how differences in PML-II between individuals may influence how they respond to virus infection, since we know that there are major differences in the outcome of apparently similar infections between one person and another. We will be testing two types of difference in PML-II: first, differences at the gene level, as a result of the different genes we inherit; and second, differences that arise in cells as a result of the environment they experience. Here we will be looking particularly at heat stress - the kind of effect that can arise naturally when someone experiences a fever - and asking whether changes in PML that result from such stress are the basis for differences in innate responses and susceptibility to virus infection that we have already seen.It is really important to unravel the ways in which innate immune responses are generated in the body. Cells being unable to respond sufficiently could mean that an infection spreads further and faster than it would have done - making you more sick. Alternatively, an innate response that becomes overly prolonged can lead to chronic inflammation, a condition which is associated with significant human diseases such as rheumatoid arthritis. Building on the work we will do to understand the involvement of PML-II in innate responses, this project will also evaluate a new strategy aimed at controlling these responses.

就像我们在天气变冷时把轻便的夏装换成冬天的衣服一样，我们的细胞也需要制造不同的蛋白质来适应不断变化的环境，比如当它们被病毒入侵时。这个项目是关于了解我们的细胞如何响应病毒感染而发生变化，特别是它们如何产生所谓的先天免疫反应。这种反应涉及细胞产生新的蛋白质，以限制病毒的生长和传播。蛋白质是由RNA分子中携带的指令产生的。这些又是通过复制细胞基因中的信息来制造的，这一过程被称为转录。因此，当细胞受到病毒感染的压力时，它会通过基因转录模式的变化做出反应。我们已经发现，一种被称为PML-II的蛋白质的行为就像一个基因的主调节器，这些基因的转录在病毒感染后迅速启动。该项目的主要目的是找出对这种蛋白质的存在做出反应的基因组的范围，以及最重要的是，这些基因与那些独立于它的基因的区别。我们计划使用最现代的技术来检查当先天免疫反应启动时，人类基因组中所有20，000个或更多基因的事件。通过这种方式，我们将获得一个系统的观点PML-II蛋白的影响，不受任何偏见的限制。从这一点出发，我们打算找出PML-II的差异如何影响他们如何应对病毒感染，因为我们知道，在一个人和另一个人之间的明显相似的感染的结果有很大的差异。我们将测试PML-II中的两种类型的差异：第一，基因水平上的差异，这是由于我们继承的不同基因造成的;第二，由于细胞所经历的环境而产生的差异。在这里，我们将特别关注热应激--当一个人发烧时自然产生的效应--并询问由这种应激引起的PML变化是否是我们已经看到的先天免疫反应和对病毒感染易感性差异的基础，揭示先天免疫反应在体内产生的方式非常重要。细胞无法做出充分反应可能意味着感染传播得更远更快-使您更加生病。或者，先天反应过度延长可能导致慢性炎症，这是一种与类风湿性关节炎等重大人类疾病相关的病症。基于我们将做的工作来了解PML-II参与先天反应，该项目还将评估一种旨在控制这些反应的新策略。