MICA: Defining the functional modes of action, and therapeutic potential of targeting, the free fatty acid receptor FFA4 in the lung.

Asthma and chronic obstructive pulmonary disorder (COPD) are two major lung diseases affecting >500 million people worldwide. Treating these two diseases in the European Union alone costs >56 billion EUROs per annum. Although there are a number of good treatments for both asthma and COPD, these are only effective in a sub-group of patients. For example, 45% of asthmatics remain uncontrolled. An additional alarming fact is that there are no drugs that can stop the progression of either asthma or COPD. There is therefore an urgent need to develop a clearer understanding of how the lung works and how to develop drugs that might relieve symptoms of human lung disease as well as prevent the progression of disease. This project aims to address these issues.
We have been working on a receptor protein in the lung that is activated by fats. This seems a little strange since the fats that activate this receptor protein come from our diet. Despite this, the receptor protein, called free fatty acid 4 (FFA4), when activated by small drug-like molecules, results in relaxation of muscle that surrounds the airways in the lung. This relaxation response opens the airways allowing more air to flow in an out of the lung. We have showed that drugs that activate FFA4 improve the function of the lungs in mouse models of asthma and COPD. These preliminary data suggest that making drugs that activate FFA4 might be a good way of treating asthma and COPD. The grant presented here will use mouse models of disease as well as tissue from human patients suffering from asthma and COPD to ask the question whether FFA4 is a good target for the development of drugs for human airway disease.
To achieve this aim we are not only drawing on our experience of the mechanisms of drug action (pharmacology) but we have also pulled together a team of expects that includes respiratory medical doctors and the drug company Astra Zeneca. Thus, with this combined expertise and excellent preliminary data, together with powerful genetically engineered mouse models we hope to reach the objectives presented in this grant.

Our aim is to - define the physiological and signalling modes of action of FFA4 in the lung and determine whether this receptor can be validated as a therapeutic target in human airway disease.

This will be achieved by addressing the following three primary objectives;
1. To understand the physiological role and modes of signalling of FFA4 in the lung
We will utilise a genetically engineered mouse line that expresses the enzyme beta-galactosidase in place of FFA4 (FFA4-KO(beta-gal)) as well as validated in-house anti-bodies to FFA4 to map the expression profile of FFA4 in the murine lung. Using a unique toolbox of FFA4 small molecule ligands together with engineered mice where the FFA4 receptor has been mutated in a manner that restricts signalling (i.e. a G protein biased FFA4 mutant) we will define the models of signalling of FFA4 in the lung. Importantly, these tools will also be employed to determine the molecular mechanism by which FFA4 mediates airway smooth muscle (ASM) relaxation in murine lung. In particular to establish if FFA4 operates directly at the level of ASM or alternatively mediates the release of a relaxation factor from lung epithelium.

2. To employ murine disease models to determine the pharmacological and signalling basis of FFA4 responses in the context of airway disease
Using an array of murine disease models that show hallmarks of human inflammatory airway disease we will test the in vivo efficacy of FFA4 selective small molecule ligands as agents for symptomatic treatment and disease modification.

3. To use clinical tissue samples and primary human cell preparations to establish the therapeutic potential of targeting FFA4 in human airway disease.
Access to a range of human lung tissue and primary cell lines (ASM and epithelial cells) from normal donors and patients with varying degrees of airway disease (both asthma and COPD) will allow us to investigate the potential of targeting FFA4 in the context of human lung disease.

Academic Beneficiaries
The G protein coupled receptor (GPCR) research is a field with wide ranging interests from basic mechanisms of cell signaling through to drug discovery. The programme of research described here covers a similar wide range of interests. Hence the grant will draw-in those members of the GPCR field that are interested in general mechanisms of cell signaling and fundamental aspects of signal transduction. Additionally, since we will be describing how FFA4 signalling operates within a physiological context the progamme will also be of impact to those basic scientists interested in physiological and whole animal GPCR responses. Specifically, the programme focuses on the action of FFA4 in the lung and therefore will be of impact to both basic respiratory scientists and respiratory clinicians. The clinical aspects of the programme, in particular, the validation of FFA4 as a novel therapeutic target in airway disease will further make an impact on research and understanding of clinical respiratory scientists.

Industrial Beneficiaries
Despite the success of GPCRs as drug targets only 15% of GPCRs in the human genome have been targeted with clinically validated drugs. There is therefore a huge unmet potential among "understudied" GPCR subtypes as clinical targets. Hence, our programme, which is aimed to test if FFA4 is a valid target in human airway disease, will be of significant interest to the pharmaceutical industry generally since it will provide fundamental principles that can be applied to other "understudied" GPCR subtypes in drug discovery. To those companies that are specifically interested in respiratory disease (for example our industrial partner Astra Zeneca) then the results from our programme will have high value since it will provide the framework for the development of novel therapeutics for the treatment of asthma and COPD.

Patient Beneficiaries
Asthma and COPD arew a major world health burdens affecting >500 million people worldwide in both developed and developing countries. Although there are current effective treatments for both asthma and COPD it is now clear that these are heterogeneous diseases and that current treatments are only effective in a subgroup of patients. For example, despite efficacious therapeutics for asthma, 45% of asthmatics remain uncontrolled. Furthermore, there are currently no treatments that prevent or modify the progression of asthma or COPD. Thus, there is an urgent need to develop novel drugs for the treatment and modification of inflammatory airway disease. This programme addresses these issues by investigating if FFA4 is a valid target for the generation of next generation drugs to treat inflammatory airway disease. A major beneficiary of this programme therefore will be patients who would benefit from novel treatments should we validate FFA4 as a target and should this target be pursued in drug develop by ourselves or by the pharmaceutical industry.

General Public
The general public are increasingly aware of the major health issues of our time. With asthma and COPD impacting on many people in the UK and beyond it is within the public interest to fund science that might relieve some of this health burden. Hence our study is likely to have a major impact on the general public by firstly demonstrating that tax payers medical concerns are being addressed by the scientific community and secondly, if our studies lead eventually to novel treatments then there will be a direct benefit to both patients and carers.