Characterisation of signal transduction pathways that restrict activation of the innate immune system to prevent inflammatory and autoimmune diseases

限制先天免疫系统激活以预防炎症和自身免疫性疾病的信号转导途径的表征

• 批准号: MR/K000985/1
• 负责人: Philip Cohen
• 金额: $ 185.54万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000985%2F1
• 关键词: Characterisation; signal; transduction; pathways; restrict

When people are infected by bacteria or viruses, the body's immune system responds immediately by producing a variety of substances that are released into the blood and mount responses to combat and eliminate these invading pathogens. This first line of defence is called the innate immune system and my research is directed at understanding how it works.Although the innate immune system is vital to combat infection, it is also a "double-edged" sword because, if switched on too strongly or for too long a period of time, or if it cannot be switched off effectively, it can cause autoimmune and inflammatory diseases. These include rheumatoid arthritis, psoriasis, lupus, ulcerative colitis, Crohn's disease, asthma and sepsis. Understanding the mechanisms that keep the innate immune system in check, and which switch it off after it has done its job, is therefore extremely important. My recent research has begun to identify several mechanisms for keeping the innate immune system in check that were not appreciated previously and one goal of my research programme is to understand how they operate in much greater detail. These studies are likely to identify components of the innate immune system that can be targeted to develop improved drugs for the treatment of autoimmune and inflammatory diseases. I am facilitating drug development through a unique collaboration that I set up in 1998 with six of the world's largest pharmaceutical companies, and which has recently been renewed until 2016. In this way, the companies are not only provided with the results of my research as soon as the discoveries have been made, but they also receive the chemicals, technologies and know-how that they need to rapidly start new drug discovery programmes and accelerate others.

当人们被细菌或病毒感染时，身体的免疫系统立即作出反应，产生各种物质释放到血液中，并产生反应来对抗和消除这些入侵的病原体。这第一道防线被称为先天免疫系统，我的研究旨在了解它是如何工作的。虽然先天免疫系统对对抗感染至关重要，但它也是一把“双刃剑”，因为如果打开太强或太长时间，或者如果不能有效关闭，它可能会导致自身免疫和炎症疾病。这些疾病包括类风湿性关节炎、牛皮癣、狼疮、溃疡性结肠炎、克罗恩病、哮喘和败血症。因此，了解控制先天免疫系统的机制以及在完成工作后关闭它的机制是非常重要的。我最近的研究已经开始确定几种机制，以保持先天免疫系统的检查，以前没有得到赞赏，我的研究计划的一个目标是了解他们如何运作更详细。这些研究有可能确定先天免疫系统的组成部分，这些组成部分可以被靶向开发用于治疗自身免疫性疾病和炎症性疾病的改进药物。我通过1998年与世界上六家最大的制药公司建立的独特合作促进药物开发，最近已延长至2016年。通过这种方式，公司不仅在发现后立即获得我的研究结果，而且还获得了快速启动新药发现计划和加速其他计划所需的化学品、技术和专业知识。

项目成果

Bill Whelan's impact on my life and career.

比尔·惠兰对我的生活和职业生涯的影响。

• DOI: 10.1016/j.mam.2015.08.001
• 发表时间: 2015
• 期刊: Molecular aspects of medicine
• 影响因子: 10.6
• 作者: Cohen P

Kinase drug discovery--what's next in the field?

• DOI: 10.1021/cb300610s
• 发表时间: 2013-01-18
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Cohen, Philip;Alessi, Dario R.
• 通讯作者: Alessi, Dario R.

Immune diseases caused by mutations in kinases and components of the ubiquitin system.

• DOI: 10.1038/ni.2892
• 发表时间: 2014-06
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Cohen P

The promise and peril of chemical probes.

• DOI: 10.1038/nchembio.1867
• 发表时间: 2015-08
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
• 通讯作者: Zuercher WJ

The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways.

• DOI: 10.1038/cdd.2017.17
• 发表时间: 2017-07
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Cohen P;Strickson S
• 通讯作者: Strickson S