Elucidation of mechanisms that restrict the activation of Toll-Like Receptors and the IL-1 receptor to prevent inflammatory and autoimmune diseases

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

Abstract

The immune system is vital for defense against microbial pathogens, such as bacteria and viruses, but if it is activated too strongly or cannot be switched off efficiently, it can cause serious tissue damage and lead to many inflammatory and autoimmune diseases. These diseases include arthritis, asthma, colitis, fibrosis, lupus, psoriasis and sepsis, which affect the lives of millions of people. It is therefore critical to not only understand the mechanisms that switch on the immune system, but also those that prevent it from being activated to strongly and those that switch it off again when it is no longer needed. Our research proposal builds on novel and exciting recent findings made by our research teams, which have advanced the understanding of how the immune system is kept under control and switched off. In the longer term, our research may lead to the development of improved drugs to treat inflammatory and autoimmune diseases. It may also help to treat some forms of cancer because the immune system has a key role in helping to destroy the tumour cells that cause cancer. With these aims in mind, we are working will both University researchers and pharmaceutical companies to launch and accelerate the development of new medicines to treat these diseases that target key controller proteins that our research has identified.

Technical Summary

We have identified novel mechanisms by which the innate immune system is kept in check to prevent the development of inflammatory and autoimmune diseases. We plan to enhance our understanding of these mechanisms, which will facilitate the development of improved ways to diagnose, prevent and treat these conditions.

One aspect of our research will be to elucidate how the ABIN family of ubiquitin-binding proteins prevent the development of inflammatory and autoimmune diseases. These studies will build on an exciting discovery that we have made, which may explain why mice-expressing a ubiquitin-binding-defective mutant of ABIN1 develop lupus. We will also elucidate why ubiquitin-binding to ABIN2 is required for the IL-1-dependent induction of cyclo-oxygenase 2 in fibroblasts, following our discovery that this pathway protects mice against intestinal inflammation and DSS-induced colitis. We will also elucidate the function of ABIN3, which is unknown.

A further aspect of our research focuses on the SIK subfamily of protein kinases, which function to restrict production of the anti-inflammatory cytokine IL-10 through a mechanism that we have defined. A major aim now is to discover how SIKs promote pro-inflammatory cytokine production and how they operate synergistically with other signalling networks. A further goal is to exploit mouse lines lacking expression and/or catalytic activity of one or more SIK isozymes, which we have made and will develop. In particular, we will investigate whether these mice are protected in several mouse models of inflammatory and autoimmune diseases. We will also investigate the effects of potent and specific small molecule inhibitors of the SIKs in these systems.

This is a multidisciplinary research programme that will exploit state-of-the-art techniques such as mass spectrometry, proteomics, signal transduction, immunology, molecular pharmacology, mouse genetics and mouse models of inflammatory and autoimmune disease.

Planned Impact

Abnormalities in protein phosphorylation and protein ubiquitylation cause many diseases including cancer and diseases of the immune system. Protein kinases, the enzymes that catalyse protein phosphorylation, have become the pharmaceutical industry's most important class of drug target with 37 kinase inhibitors approved for clinical use since 2001, and hundreds more at various stages of clinical trials. Gleevec, the first kinase inhibitor approved for clinical use, has transformed a fatal leukaemia to a manageable condition. The JAK inhibitors Tofacitinib and Ruxolitinib approved during the last five years, for the treatment of rheumatoid arthritis and myelofibrosis, respectively, are the first kinase inhibitors approved outside the field oncology. Sales of kinase inhibitors now exceed $US 30 billion per annum.

The recent research of our laboratories on the role of SIK family members in controlling macrophage polarity, has attracted considerable interest in these protein kinases as drug targets for the treatment of macrophage-driven inflammatory diseases. Several pharmaceutical companies and academic drug discovery groups are now working to develop drugs that inhibit SIKs which, if successful, will benefit many patients afflicted with these diseases and generate revenue for the companies that develop and sell them. Over the past two years alone, we have provided 16 academic laboratories with 36 reagents we have generated from our SIK-related research, while two companies have purchased 18 of our reagents. Our research has also had a positive impact on the Support companies that market the reagents produced by my research team.

In 1998 I founded the Division of Signal Transduction Therapy (DSTT), which became the largest collaboration between academia and the pharmaceutical industry in Europe. It continues to this day with fundng renewed for a fifth time from July 2016-June 2020, a clear demonstration of its value to pharma. The DSTT is widely regarded as a model for effective interaction between academia and industry, and has received a Queen's Anniversary Award for Higher Education. Through this collaboration the participating companies obtain rapid access to the result of my research and that of my co-applicant Simon Arthur, as well as the reagents and technologies that that are produced and developed by our labs. I am and will continue to be the Deputy Director of the DSTT.

Like protein phosphorylation, protein ubiquitylation regulates most aspects of cell life and is an emerging area of drug discovery (Cohen and Tcherpakov, 2010, Cell 143, 686-693). To stimulate progress in this area, I 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. SCILLS was merged with the MRC Protein phosphorylation and Ubiquitylation Unit (MRC-PPU) at Dundee in 2013. These developments let to the founding of Ubiquigent Ltd, a new UK-listed company in Dundee, which markets proteins, assays and services developed by my research team and by other research groups in the MRC-PPU. A significant proportion of the shares in Ubiquigent are owned by the MRC and the University of Dundee, which may acquire a substantial value when Ubiquigent becomes a listed company on a stock exchange.
 
Description Arthritis UK
Amount £261,068 (GBP)
Funding ID MP/19518 
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
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 Public
Country United Kingdom
Start 04/2018 
End 03/2023
 
Description MRC DTP I-Case studentship
Amount £87,697 (GBP)
Funding ID MR/N013735/1/ 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 02/2022
 
Description Evaluation of the efficacy of drugs that switch off the protein kinase SIK for the treatment of asthma and other diseases 
Organisation Beatson Institute for Cancer Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Testing whether SIK inhibitors prevent disease in animal models of asthma, lung fibrosis and arthritis.
Collaborator Contribution Development and synthesis of SIK inhibitors.
Impact Collaboration with Japanese Pharmaceutical company. Discussion with major UK pharmaceutical company.
Start Year 2018
 
Description Role of ALPK1 in regulation of innate immunity 
Organisation University of Oxford
Department Kennedy Institute of Rheumatology
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis of the bacterial metabolite ADP-heptose; use of cell signalling technology and mass spectrometry to understand how ADP-heptose signals.
Collaborator Contribution Generation of ALPK1 knock-out mice, mouse model of colitis.
Impact ADP-heptose produced and shipped to Oxford.
Start Year 2019
 
Description Role of SIKs in plasma cell differentiation 
Organisation University of Leeds
Department Leeds Institute of Cancer & Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided tissues from SIK kinase-inactive mice; Ran in vivo immunisation models in SIK kinase-inactive mice and provided tissues for analysis
Collaborator Contribution Analysis of B cell markers, plasma cell differentiation and signalling
Impact Poster presentation at Immunology 2018 conference (by collaborators student) PhD award (collaborators student)
Start Year 2017
 
Description British Council sponsored lecture tour of India 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave 6 lectures over an 8 day period, 2 in Kolkata, two in Guwahati and 2 in Mumbai. In Kolkata I lectured at the Indian Institute for Chemical Biology and talked with staff and students about my current research on the innate immune system. I also lectured to doctors, patients and staff at the Tata Medical Centre, one of the world's largest cancer hospitals, about the development of kinase inhibitors for the treatment of cancer. In Guwahati I lectured at the Indian Institute of Technology and had discussions with staff and students and gave a further lecture to a Dhwani an association of medical doctors about the therapeutic value of kinase inhibitors. In Mumbai, I gave a lecture to undergraduates at the KJ Somaiya College of Science and Commerce and lectured and had discussions with doctors and research staff at the Tata Memorial Centre
Year(s) Of Engagement Activity 2019
 
Description Keynote Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The International Society for Systemic and Auto-Inflammatory Disseases (Genoa, Italy, March 31st - April 2nd 2019
Year(s) Of Engagement Activity 2019
 
Description Keynote Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International Meeting on Diabetes and Metabolic Disorders, Indiana University, USA
Year(s) Of Engagement Activity 2019
 
Description Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The biannual UK and Ireland meeting on NF-?B (Liverpool, UK, October 2019)
Year(s) Of Engagement Activity 2019
 
Description Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact MRC Centre for Reproductive Health, University of Edinburgh (July 30th 2019)
Year(s) Of Engagement Activity 2019
 
Description Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Lecture at AstraZeneca, Cambridge UK (July 23rd 2019)
Year(s) Of Engagement Activity 2019
 
Description Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lecture to celebrate the Centenary of the founding of The University of Wales Cardiff School of Pharmacy (Nov. 20th 2019)
Year(s) Of Engagement Activity 2019
 
Description MacTV BBC Alba Documentary on Parkinson's 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A documentary on Parkinson's that will also include a segment on the MRC PPU's Parkinson's research as well as an interview with myself on the School of Life Sciences at the University of Dundee.

To be aired on BBC Alba, the BBC's Gaelic Channel, on Monday 18th March 2019
Year(s) Of Engagement Activity 2019
 
Description The Edgar da Cruz e Silva Memorial Lecture. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact SIGNAL 2019, Algarve, Portugal The Edgar da Cruz e Silva Memorial Lecture.
Year(s) Of Engagement Activity 2019
 
Description The GAP summit, Trinity College Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I participated in a discussion about "The road from Academia to Industry" with Sir Greg Winter and Stephen Caddick at the GAP summit, Trinity College Cambridge in April 2018. This was a meeting of 100 selected PhD students who are from across the world who are interested in Biotechnology
Year(s) Of Engagement Activity 2018
 
Description The Great Lectures series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Great Lectures series - British Council sponsored lecture tour of India. Six lectures given at Universities and Hospitals in Kolkata, Guwahati and Mumbai - February 2nd-12th 2019
Year(s) Of Engagement Activity 2019
 
Description The Special Symposium Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The 60th annual meeting on Advances in Biological Regulation, Bologna, Italy (September 2019)
Year(s) Of Engagement Activity 2019