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

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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.