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

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.

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.

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.