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

先天免疫系统对损伤（如感染）反应的一个关键阶段是在病原体周围引发炎症。炎症反应是必要的，允许免疫细胞募集到身体的区域窝藏病原体和刺激进一步的免疫反应，旨在消除病原体和解决感染。这一过程对于引发有效的免疫反应和迅速消除入侵的病原体至关重要，并将持续数小时至数天。然而，在某些情况下，炎症不容易消除，并无限期地持续下去，成为疾病的一个原因。慢性炎症对我们的健康是有害的，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，也会导致癌症的发展。Hanahan和Weinberg指出，六分之一的恶性肿瘤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是关键，以便能够抑制致癌炎症并阻碍肿瘤生长。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。这个项目的目的是，首先，确定不可降解的泛素修饰（添加到蛋白质上的小标签，可能改变它们的状态或引发功能）如何促进炎症反应，并在机制水平上进行调节。其次，该项目将旨在确定这些机制如何在肿瘤生长时发生变化，而不是对病原体的主要反应。

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.