Ubiquitin signalling in innate immune responses to pathogens and chronic inflammation in cancer

对病原体和癌症慢性炎症的先天免疫反应中的泛素信号传导

• 批准号: 2436427
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2436427
• 关键词: Ubiquitin; signalling; innate; immune; responses

A key phase of the innate immune system's response to insults (e.g. infection) is to elicit inflammation around the area of the pathogen. Inflammation responses are necessary to allow for the recruitment of immune cells to the region of the body harbouring the pathogen and to stimulate further immune responses that aim to eliminate the pathogen and resolve infection. This process is essential to elicit efficient immune responses and rapidly eliminate invading pathogens and will last between hours and days. In some instances, however, inflammation is not resolved readily and lasts indefinitely becoming itself a cause of disease.Chronic inflammation can be detrimental to our health on account of the molecules released as part of the immune response also having the capacity to damage our own cells and tissues and also with regards to cancer development. 1 in 6 of all malignancies are thought to be the result of chronic infection, with persistent tumour-promoting inflammation being a Hallmark of Cancer, as laid out by Hanahan and Weinberg. On the other hand, inflammation in the tumour microenvironment can also facilitate anti-tumour immune responses. It is, therefore, key to determine the mechanisms that regulate inflammation in order to be able to supress oncogenic inflammation and hinder tumour growth. A detailed view as to how and when inflammation becomes detrimental may pave the way for novel strategies in cancer therapy. The aim of this project is, firstly, to determine how non-degradative ubiquitin modifications (small tags added to proteins which may alter their status or elicited functions) facilitate the inflammatory response and are regulated at a mechanistic level. Secondly, this project will aim to determine how these mechanisms are altered in response to a growing tumour compared to primary responses to pathogens.

先天免疫系统对损伤（例如感染）的反应的关键阶段是引发病原体区域周围的炎症。炎症反应是必需的，以允许将免疫细胞募集到携带病原体的身体区域，并刺激旨在消除病原体和解决感染的进一步免疫反应。这一过程对于引发有效的免疫反应和快速消除入侵病原体至关重要，并将持续数小时至数天。然而，在某些情况下，炎症并不容易解决，并且无限期地持续下去，成为疾病的原因。慢性炎症可能对我们的健康有害，因为作为免疫反应的一部分释放的分子也有能力破坏我们自己的细胞和组织，也与癌症的发展有关。据Hanahan和温伯格所述，所有恶性肿瘤中有1/6被认为是慢性感染的结果，持续的促肿瘤炎症是癌症的标志。另一方面，肿瘤微环境中的炎症也可以促进抗肿瘤免疫反应。因此，确定调节炎症的机制以能够抑制致癌性炎症并阻碍肿瘤生长是关键。关于炎症如何以及何时变得有害的详细观点可能为癌症治疗的新策略铺平道路。该项目的目的是，首先，确定非降解性泛素修饰（添加到蛋白质中的小标签，可能会改变其状态或引发功能）如何促进炎症反应，并在机制水平上进行调节。其次，该项目旨在确定这些机制如何改变对肿瘤生长的反应，而不是对病原体的主要反应。