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

Lead Research Organisation: University of Dundee
Department Name: School of Life Sciences

Abstract

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.

Technical Summary

We propose to develop our understanding of novel mechanisms we have identified that keep the innate immune system in check and prevent autoimmune and inflammatory diseases. Understanding how this system is controlled and its de-regulation in disease is a prerequisite for the development of new treatments for these conditions.

We will study a protein kinase subfamily that we have found to restrict the production of anti-inflammatory cytokines. We will identify which members of this subfamily mediate this effect and the underlying molecular mechanism. We will develop specific inhibitors of these kinases via collaborations with academic colleagues as well as via a unique collaboration with the pharmaceutical industry, which we have renewed until 2016.

We have discovered that the IKK-related kinases (IKKepsilon and TBK1) restrict pro-inflammatory cytokine production by inhibiting the activation of NFkappaB. We have also identified additional, putative substrates of these kinases, which suggest that they restrict innate immune signalling pathways in other ways. We will elucidate these mechanisms and establish their importance in keeping innate immunity in check.

We will develop our discovery that polyubiquitin-binding to ABIN1 and ABIN2 prevents lupus and protects against colitis, respectively. We will elucidate how ABIN2 protects against colitis and the molecular mechanism(s) by which ABIN1 and ABIN2 restrict innate immune signaling pathways. We will also investigate whether the deubiquitylase activity of A20, a protein that interacts with ABIN1 and ABIN2, is critical for the functions of the ABINs.

This multidisciplinary research programme will exploit state-of-the-art techniques in protein chemistry, enzymology, mass spectrometry, signal transduction, immunology, mouse genetics and molecular pharmacology and should lead to the elucidation of key mechanisms that restrict the activation of innate immune signaling pathways.

Planned Impact

Abnormalities in protein phosphorylation cause cancer and other diseases and protein kinases have become the pharmaceutical industry's most important class of drug target. 16 kinase inhibitors have been approved for cancer since 2001, which include Gleevec that has transformed a fatal leukaemia to a manageable condition. The current market for kinase therapies is $15 billion p.a. with 200 more kinase inhibitors in clinical trials. The JAK inhibitors Tasocitinib and Ruxolitinib should be approved for treating rheumatoid arthritis in 2012, the first kinase inhibitors approved outside oncology. My research on innate immunity is therefore becoming of increasing interest to pharma. They and the companies that market the reagents I produce will be the non-academic beneficiaries of my research.

In 1998 I founded the Division of Signal Transduction Therapy (DSTT), which has become the largest collaboration between academia and the pharmaceutical industry. It is widely regarded as a model for effective interaction between academia and industry, and received a Queen's Anniversary Award for Higher Education in 2006. Agreement to renew funding for the DSTT for a further 4 years from July 2012 has just been agreed with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Johnson and Johnson, Merck-Serono and Pfizer, a clear indication of its value to Pharma. Through this collaboration the companies obtain rapid access to the MRC Protein Phosphorylation Unit's (MRC-PPU) unpublished results, reagents and technologies and the first right to licence the IP generated.

Upstate Inc. was set up in Dundee in 1999 to build on a successful, commercial relationship with the MRC-PPU that began in 1995. Upstate Dundee exploited the kinase profiling technology I developed very successfully and employed 125 by 2004 when it was acquired by Serologicals for $205 milion. Subsequent acquisions by Millipore and then Merck KGaA created Merck-Millipore in 2010, who market 300 products developed by the MRC-PPU, many generated by my research team. This is an efficient way of distributing my reagents to thousands of laboratories worldwide while also generating significant revenue for the MRC-PPU. In 2005, these royalties were used to rehouse the MRC-PPU in the new Sir James Black Centre saving the MRC £4.5 million.

Like phosphorylation, ubiquitylation regulates almost all aspects of cell life and is becoming a major area of drug discovery (Cohen and Tcherpakov, 2010, Cell 143, 686-693). In 2008 I therefore founded the Scottish Institute for Cell Signaling (SCILLS) the world's first Unit dedicated to the study of ubiquitylation with funding of £10 million from the Scottish Government. The Unit has developed rapidly and now has 8 PIs and 55 scientific and support staff. For this reason, the field of the DSTT will change in July 2012 from "kinases and phosphatases" to "kinases and the ubiquitin system".

In 2009, I persuaded US-based Stemgent Inc. to found Ubiquigent Ltd in Dundee, which markets proteins, assays and services developed by SCILLS. 10% of the shares are owned by the MRC and 10% by the University of Dundee, which will be worth a substantial sum if Ubiquigent is listed on a stock exchange. In addition, Ubiquigent market components of the ubiquitin system produced by my research team. This contributes to its development and creates a royalty stream for SCILLS, which is already becoming significant.

I have recently identified the SIK subfamily as kinases that suppress the production of IL-10 and other anti-inflammatory molecules. The proposed research will lead to the development specific SIK inhibitors with potential for the treatment of inflammatory and autoimmune diseases. If successful, this will generate substantial revenue for the MRC-PPU and College of Life Sciences at Dundee, and eventually benefit patients with inflammatory and autoimmune diseases.

Publications

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Arrowsmith CH (2015) The promise and peril of chemical probes. in Nature chemical biology

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Caster DJ (2013) ABIN1 dysfunction as a genetic basis for lupus nephritis. in Journal of the American Society of Nephrology : JASN

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Clark K (2013) Molecular control of the NEMO family of ubiquitin-binding proteins. in Nature reviews. Molecular cell biology

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Cohen P (2015) Bill Whelan's impact on my life and career. in Molecular aspects of medicine

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Cohen P (2014) The TLR and IL-1 signalling network at a glance. in Journal of cell science

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Cohen P (2018) Ubiquitin chains as second messengers. in Nature reviews. Molecular cell biology

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Cohen P (2013) Kinase drug discovery--what's next in the field? in ACS chemical biology

 
Description Another grant from Ono
Amount £419,000 (GBP)
Organisation Ono Pharmaceutical 
Sector Private
Country Japan
Start 01/2017 
End 12/2019
 
Description Arthritis UK
Amount £261,068 (GBP)
Funding ID MP/19518 
Organisation Versus Arthritis 
Start 04/2017 
End 12/2019
 
Description AstraZeneca
Amount £32,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 09/2018 
End 02/2022
 
Description BBSRC EastBio studentship
Amount £94,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description Elucidation of mechanisms that restrict the activation of Toll-like receptors and the IL-1 receptor to prevent inflammatory and autoimmune disease
Amount £1,229,672 (GBP)
Funding ID MR/R021406/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 03/2023
 
Description Grant to MRC funded postdoc in lab
Amount £15,000 (GBP)
Organisation Tenovus 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2017
 
Description MRC DTP I-Case studentship
Amount £87,697 (GBP)
Funding ID MR/N013735/1/ 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2018 
End 02/2022
 
Description MRC DTP I-Case studentship funding from AstraZeneca
Amount £32,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 09/2018 
End 02/2022
 
Description New research grant from the pharmaceutical industry
Amount £200,000 (GBP)
Organisation Ono Pharmaceutical 
Sector Private
Country Japan
Start 01/2016 
End 12/2018
 
Description PhD
Amount £113,156 (GBP)
Funding ID PHD-770/2014 
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 08/2019
 
Description The role of CREB in limiting inflammation
Amount £202,260 (GBP)
Funding ID 19518 
Organisation Versus Arthritis 
Start 01/2011 
End 12/2013
 
Description Wellcome Trust Senior Investigator Award
Amount £1,674,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2018
 
Description David Powell 
Organisation University of Kentucky
Department Magnetic Resonance Imaging and Spectroscopy Center
Country United States 
Sector Academic/University 
PI Contribution We have provided David Powell with a lupus prone mouse line that we have developed
Collaborator Contribution David Powell is a nephrologist who has analysed the kidney damage that occurs in these mice in great detail
Impact .
Start Year 2013
 
Description Henning Walczak 
Organisation University College London
Department Department of Geography
Country United Kingdom 
Sector Academic/University 
PI Contribution We are studying TLR3 signalling using macrophages from HOIP knock-out mice provided by henning Walczak
Collaborator Contribution .Provision of HOIP knockout mice
Impact .
Start Year 2015
 
Description Iain Macinnes 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration has only just been set up. The aim is to test a novel idea about how to identify patients destined to develop lupus before they are aware that this will happen.
Collaborator Contribution .
Impact .
Start Year 2017
 
Description Nathanael Gray 
Organisation Dana-Farber Cancer Institute
Country United States 
Sector Hospitals 
PI Contribution We have used many protein kinase inhibitors developed by Nathanael Gray to advance a number of our projects
Collaborator Contribution Provision of protein kinase inhibitors with defined specificities
Impact Several papers have been published (see publication list). The projects are multidisciplinary and combined Nathanael Gray's expertise in Chemistry with our expertise cell signalling and the innate immune system.
Start Year 2013
 
Description Ono Pharmaceutical Company Collaborative Research Project 
Organisation Ono Pharmaceutical
Country Japan 
Sector Private 
PI Contribution Investigating the therapeutic potential of inhibiting the SIK family of protein kinase
Collaborator Contribution Production of compounds and animal studies, secondment of staff from Japan to Dundee
Impact Increased research funding for my laboratory over the next two years. The collaboration is inter disiplinary involving mouse genetics, animal studies, cell signaling, biochemistry and chemical biology.
Start Year 2016
 
Description Steve Ley 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are studying the mechanism by which mice expressing a ubiquitin-binding defective mutant of ABIN2 develop intestinal inflammation
Collaborator Contribution Steve Ley our collaborator has provided an antibody that recognises ABIn2 and has provide advice that has been useful in advancing this project
Impact .
Start Year 2016
 
Description Vikram Rao 
Organisation Pfizer Inc
Country United States 
Sector Private 
PI Contribution We have used mouse genetics to validate the protein kinases IRAK1 and IRAK4 as drug targets for the treatment and/or prevention of lupus
Collaborator Contribution Vikram Rao has providing small molecule inhibitors of these protein kinases to studying the physiological roles of these kinases and to test their efficacy in a mouse model of lupus
Impact A paper has been written and submitted for publication
Start Year 2013
 
Description 8th World Conference on Waldenstrom's Lymphoma 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact On the evening of August 16th Philip Cohen gave the closing lecture of the 8th International Workshop on Waldenstrom's Lymphoma in the Churchill rooms of the Houses of Parliament in London. Waldenstrom's lymphoma is caused by mutations in the protein MyD88, and 95% of the patients who are afflicted by this disease express the same mutant in which the leucine residue at position 265 is changed to proline. MyD88 is an essential adaptor protein in the signalling networks that are triggered by the binding of bacterial and viral components to Toll-Like Receptors or by the interaction of interleukins 1, 18 and 33 with their receptors.


Philip's talk to an audience that mainly comprised patients with Waldenstrom's lymphoma, their physicians, relatives and friends, focused on how MyD88 was discovered, and its key role in the innate immune system that is vital for protection against infection by microbial pathogens, especially during childhood. He also explained how the hyper-activation of the MyD88-dependent signalling network can lead to autoimmune diseases, such as lupus, and how its constitutive activation caused by the MyD88[Leu265Pro] mutation leads to lymphoma. The talk was followed by a formal dinner in the Churchill rooms, at which Philip and Tricia Cohen were the guests of honour.
Year(s) Of Engagement Activity 2014
 
Description Demonstrating practical experiments to primary school children 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 Postdocs employed on the grant (Marta Lopez-Pelaez & Juanma Ortiz-Guerrero) showed 10-12 year old children at Baldragon Academy, Dundee how to identify blood types, assay enzymes and demonstrated the concepts of pH, muscle fatigue and the reflex actions of the brain in 5 seperate visit to the school during 2015. In a further visit to St Pius school, Juanma explained to 7-8 year olds what microbes are and the importance of washing their hands.
Year(s) Of Engagement Activity 2015
 
Description Interview with ZDF (German National Public Broadcasting) Regarding Scottish Referendum 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact ZDF wished to interview Professor Cohen regarding the risks for life sciences in an independent Scotland for their European affairs programme that wished to discuss an economic case for and against independence.


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.zdf.de/ZDFmediathek#/hauptnavigation/startseite
 
Description Lecture at the Orkney International Science Festival 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Sir Philip Cohen gave a lecture at the Orkney Science Festival. Entitled "Protein Kinase Inhibitors The Major Drugs of the 21st Century". The lecture described the remarkable impact that these drugs are having on the treatment of some cancers and discussed their likely future impact on the treatment of inflammatory and autoimmune diseases. The lecture also explained how fundamental research performed in the MRC Protein Phosphorylation and Ubiquitylation Unit had contributed to this area and helped to change the perception of protein kinases as drug targets.

The audience, consisting of locals, as well as an international contingent of visitors, was engaged and asked numerous questions about the cellular processes Professor Cohen spoke of.
Year(s) Of Engagement Activity 2015
 
Description New Drugs for the 21st Century 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "Philip Cohen gave a talk about kinase drug discovery to the Scotland International Group at the Gleneagles Hotel Scotland on Friday November 29th 2013. Entitled "New Drugs for the 21st Century". The audience of 60 included the CEOs and CFOs of 20% of the UK's FTSE 100 companies, the Brazilian and Russian Ambassadors, the former UK Ambassador to the USA, the former Secretary General of NATO), Sir the former head of UK Government Operations, and Scotland's only two billionaires."


Sir Philip's talk stimulated much discussion as he recounted the research being undertaken in Dundee and the potential of many of the targets torwards therapeutic development.
Year(s) Of Engagement Activity 2014
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I gave the Pehr Edman Edman Lecture to the general public at St Vincent's Institute, Melbourne, Australia in June 2016
Year(s) Of Engagement Activity 2016
URL https://www.svi.edu.au/news/signals_of_success_the_2016_pehr_edman_lecture/
 
Description Public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact My talk to the general public at the Australian Academy of Sciences in Canberra in May was broadcast live on the Australian Academy of Sciences internet system.
Year(s) Of Engagement Activity 2016
URL https://aas.eventsair.com/QuickEventWebsitePortal/science-at-the-shine-dome-2016/sats2016/Agenda/Age...
 
Description Publicity arising from the new collaboration with Ono Pharmaceuticals 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Following a press release, Philip Cohen was interviewed by Scottish Television, which appeared on Scottish Tv in the evening. He was also interviewed by two local Dundee radio stations, Wave1 and Radio Tay, and these interviews were broadcast throughout the day. Newspaper articles appeared in the Dundee Evening Telegraph and the Dundee Courier.
Year(s) Of Engagement Activity 2016
 
Description Scotland: For Richer or Poorer? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Professor Sir Philip Cohen will be featured on Robert Peston's BBC2 Documentary 'Scotland: For Richer or Poorer' airing tonight at 9pm on BBC2. How will independence affect Dundee's reputation for excellence in life sciences?


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/iplayer/episode/b049b89z/scotland-for-richer-or-poorer
 
Description Scottish Referendum - Open Letter 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "A group of eminent Scottish medical experts have warned that independence would seriously damage research funding for Scotland's universities and medical schools.

The open letter from 14 experts, including senior staff from all five of the country's main medical schools, said they had ""grave concerns"" that Scotland's world-leading biomedical and life sciences research would suffer if Scotland ""sleepwalks"" into leaving the UK.

The letter, coordinated by Sir David Carter, a former chief medical officer in Scotland, said Scottish universities did disproportionately well out of the UK's research funding system and from the UK's charitable and medical foundation grants.
"


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.theguardian.com/politics/2014/may/23/scottish-independence-research-funding-medical-exper...
 
Description Student's important protein discovery could help fight cancer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Jiazhen Zhang, a research student in Professor Sir Philip Cohen's laboratory at the University of Dundee, has uncovered how the protein complex, called NF-?B, is activated. The results are published in July, 2014.


Research being undertaken in the Cohen lab was discussed by the broader lay community in an effort to share the impact of these studies
Year(s) Of Engagement Activity 2014
URL http://news.stv.tv/tayside/282195-jiazhen-zhang-at-university-of-dundee-publishes-research-on-nf-b/
 
Description TV interview - Brexit 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An interview that I gave to a German TV channel about the potential impact of Brexit on Science was broadcast in Germany in June 2016
Year(s) Of Engagement Activity 2016
 
Description Talk to general public in Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I gave a talk on my research career to the general public in June 2016 at Universidad Autonoma Madrid
Year(s) Of Engagement Activity 2016
 
Description Teaching young children about microbes and the immune system 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Nicola Darling and Kristopher Clark, postdoctoral researchers employed on the grant, participated in an event called "Incredible Immunology", which was a two day public outreach programme, organised by the School of Life Sciences at the University of Dundee. It took place at the Dundee Science Centre and was aimed at introducing the immune system and the ways in which research is carried out in this field. The first day was targeted at primary school children and about 125 attended, whilst the second day was attended by members of the general public, mostly families.

Nicol Darling also participated in Open Doors Day in which the School of Life Sciences at the University of Dundee shows the general public around the building. As part of this event members of the public were invited to learn more about the research being carried out at the MRC Protein Phosphorylation and Ubiquitylation Unit with about 100 people attending. The main topics were the brain and cancer introduced through interactive games and opther activities.

Nicola Darling was also involved in teaching 160 S1 pupils (aged 11-12 years) at the Baldragon Academy high school. The aim of her class on was to help the students to improve their understanding of acids, alkalis and pH, and to encourage their enthusiasm for science by performing experiments. In addition Nicola demonstrated a more complex experiment and answered questions from the children about careers in science.
Year(s) Of Engagement Activity 2015