Centre for Translational Pharmacology

Centre for Translational Pharmacology

Aim:
To determine the mechanistic action of drugs in the context of human disease with the aim of establishing novel pharmacological paradigms that will result in the rational design of next generation drugs.

International excellence:
The Centre aims to be a beacon of excellence recognised for world leading research in translational pharmacology. It will draw on and further develop the strong internal and external links facilitated by both extensive academic networks and industrial partners and will be underpinned by access to clinical expertise, patient samples and clinical trials. As such the Centre for Translational Pharmacology engages with the very best researchers and, in so doing, link each of independently funded Fellows, new investigators, students and clinical training Fellows with globally leading research teams in both academia and industry to maximise training opportunities and delivery.

National hub:
The Centre will operate as a hub for a national strategy for the development and application of novel pharmacological approaches to the treatment of human disease and in the training of next generation leaders in translational pharmacology. The Centre will place the UK at the heart of the renaissance in molecular pharmacology drive by new methodological and animal models, the availability of human patient samples and sophisticated imaging modalities (both animal and human) and rapid development of approaches to co-ordinate data streams emerging from next generation sequencing and the opportunities so presented for patient-stratified and selective pharmacological treatments. The Centre will aim to be inclusive and reach out to support and assist groups across the UK.

Industrial partnership:
Through formal links with clear funding streams the Centre cultivates strong industrial partnerships that exemplify the very best in academic industrial relations. These form an international academic/industrial network that will develop pre-clinical (pre-competitive) programmes to full scale, independently funded, drug discovery programmes with line of sight to the clinic.

Exemplar projects:

• BBSRC funded Industrial Partnership Award scheme (£1.2M) with Astra Zeneca to investigate the therapeutic potential of the free fatty acid receptor family.
• Asta Zeneca funded GLAZgo Discovery Centre (http://www.glazgodiscoverycentre.co.uk/) (£5M) lead by Prof Iain McInnes and Dr Carl Goodyear to identify novel targets in inflammatory disease.
• Open Innovation initiative (https://openinnovation.astrazeneca.com/) established with Asta Zeneca to target free fatty acid receptors.
• MRC funded Industrial Collaborative Award (MICA) (£1.1M) with Eli Lilly to target the muscarinic receptor family in the treatment of neurodegenerative disease.
• MRC CASE studentships with Eli Lily. 
• Heptares Therapeutics funded programme to de-risk hard to target GPCRs through an Opportunities in Receptor Biology for Industrial Translation ‘ORBIT’ (http://www.heptares.com/orbit/) award.

Other industrial partners include:

  • Galapagos
  • Calden Therapeutics
  • GlaxoSmithKline


Training:
The Centre has a strong training focus aimed at developing the next generation leaders in the field of basic and clinical pharmacology. This training extends substantially beyond Ph.D. programmes to involve post-doctoral and Fellowship training (both basic and clinical scientists) allowing for exchange programmes with the worlds leading laboratories. This is exemplified by the Collaborative Award currently held by Andrew Tobin with the Wellcome Trust that brings together a network of the leading research labs in the area of muscarinic receptor pharmacology and neurodegenerative disease.

Focus on G protein coupled receptors (GPCRs)

GPCR-based therapies
Building on the laboratories of Tobin and Milligan as well as the outstanding MRC-funded research in chemokine receptor biology in Glasgow the MRC Centre focuses on translational pharmacology related to GPCRs. This links to the recent re-invigoration of GPCRs as therapeutic targets by the pharmaceutical and biotechnology industries is based on the development and understanding of novel ligand modalities at GPCRs, including allosterism and bias, as well as the extension of therapeutic ligands at GPCRs from small molecule drugs to biologics. The Centre works GPCR based therapies in a number of indications including inflammatory, metabolic, respiratory and neurodegenerative disease.

Inflammatory disease
The excellence in both understanding the biology of inflammatory disease and in assessing the effectiveness of treatments in Glasgow, particularly associated with osteoarthritis, lung inflammatory disorders such as asthma and COPD and gut inflammatory disease, in concert with the extensive funding to the Tobin and Milligan labs from the BBSRC, often in partnership with AZ, to understand the mechanistic basis of GPCR function in these areas, forms the basis of a strong drive to understanding the impact of GPCR signalling and GPCR-based intervention strategies in human inflammatory disease. Moreover, a growing appreciation that low grade chronic inflammation underlies further co-morbid pathologies including metabolic disease and obesity, as well as areas of cardiovascular disease and diseases of the aging CNS, means that the Centre will link directly to core clinical strengths in Glasgow. This area will be underpinned by existing BBSRC funding to Tobin and Milligan, MRC funding in inflammatory disease at Glasgow, the GLAZgo discovery centre, and funding in partnership with Astra Zeneca.

Neurodegenerative disease
In partnership with Eli Lilly and key researchers at Monash University the Tobin laboratory has been developing novel GPCR-based therapies for the symptomatic treatment, and disease modification, of neurodegenerative disease. These partnerships underpin this key area of focus for the proposed MRC Centre.

Novel high value GPCR targets
There is a growing interest in the GPCR drug discovery field of the significant number of orphan and/or poorly understood GPCRs that might represent highly fruitful areas of drug discovery. These include the free fatty acid receptors in obesity, GPR35 in hypertension and GPR84 in brain injury such as stroke. The Centre will work with industry to validate these “hard to target” receptors and establish the therapeutic value of these receptor classes. This area is currently underpinned by support from Astra Zeneca as well as the BBSRC and has generated interest from companies such as Heptares Inc.

Metabolic disease
The Centre currently has considerable interest in the physiological and pathophysiological role of the free fatty acid receptor family (FFA1-4) as well as other receptors that respond to fatty acids such as GPR84 and GPR35. These receptors are often linked with the regulation of glucose homeostasis, adipose function and feeding behaviour and are considered high value targets for the treatment of metabolic diseases including type 2 diabetes and obesity. The Centre has a number of collaborative programmes with industrial partners such as Astra Zeneca and Galapagos to fully investigate these targets.

Respiratory disease
Building out of the interest of the Tobin laboratory in muscarinic receptor signalling in airway smooth muscle (ASM) the Centre has an interest in novel mechanisms that regulate lung function. This includes the possibility that free fatty acid receptors that are intriguingly expressed in the lung, can regulate ASM contraction. In collaboration with a number of the UKs leading respiratory basic and clinical scientists the Centre aims to validate these novel GPCR targets for the treatment of human lung diseases such as asthma and COPD.

Infectious disease
Linking the drug discovery activity of the Tobin group in malaria with excellence in parasitology research in Glasgow, particularly in the Wellcome Trust Centre for Molecular Parasitology, provides an ideal opportunity for translational pharmacology to be applied to malaria drug discovery within the Centre. The fundamental principles established through the extensive programmes within the Centre could be directly applied to infectious diseases through the links with the parasitology community in Glasgow and provide a unique opportunity for step changes to the approaches of drug discovery in this area of unmet global clinical need.

Novel anti-malaria targets
Underpinned through funded collaborations with GSK, MRCT and the MRC Unit the Gambia, and supported by a University of Glasgow LKAS-fellowship the Centre will focus on using chemical genetic approaches in concert with proteomics and phospho-proteomics to determine protein kinase targets for the treatment and transmission blocking of P. falciparum. Furthermore, in line with WHO initiatives to reduce the burden of P. vivax the Centre uses novel chemical entities emerging from the P. falciparum studies as a spring broad to target essential protein kinase pathways in P. vivax. The aim is to validate targets that are common in P. falciparum and P. vivax, and develop drug candidates that hit both parasite species.

Mechanisms of malaria resistance
The Tobin laboratory is currently part of a world network of laboratories aimed at establishing the mechanisms of malaria drug resistance. This network is led by David Fidock (Columbia University, New York, USA) and the Centre will contribute to this network by proteomic analysis of resistant parasite strains particularly from Cambodia.

Institute of Cancer Sciences

Dr Rob Insall
Professor Jim Norman 

Institute of Cardiovascular and Medical Science

Professor George Baillie
Professor Mandy MacLean
Dr Stuart Nicklin
Professor Godfrey Smith
Professor Rhian Touyz

Institute of Health and Wellbeing 

Dr Jonathan Cavanagh

Institute of Infection, Immunity and Inflammation

Professor Mike Barrett
Dr Carl Goodyear
Professor Gerry Graham
Professor Iain McInnes
Dr Simon Milling
Professor Rob Nibbs

Institute of Molecular, Cell and Systems Biology

Professor Matt Dalby
Professor Shireen Davies
Professor Julian Dow

Institute of Neuroscience and Psychology

Dr Stuart Cobb
Professor Andrew Todd

College of Physics and Astronomy

Professor Andrew Harvey
Dr Jonathan Taylor