Nearly a third of people in the UK will suffer an allergy at some point in their lives, yet treatments have barely improved. Mast cells—immune cells that overreact to harmless triggers like pollen or pet fur—drive these reactions by flooding with calcium through tiny surface pores called CRAC channels. This project will map the molecular machinery that controls those pores in healthy mast cells and then see how that machinery goes wrong in two common allergic diseases: nasal polyposis and dermatitis. The researchers have already developed a new strategy to dial down mast cell activity by targeting these calcium channels. They will now test that strategy in a system that mimics real human disease, not just a petri dish. If it works, the approach could lead to drugs that calm allergic inflammation without the broad side effects of current treatments. Even if the therapeutic strategy needs refinement, the fundamental science here—understanding exactly how calcium entry triggers mast cell activation—will fill a gap that has stalled progress in allergy medicine for decades.
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Allergies have reached epidemic levels in the UK, with almost 30% of the population estimated to suffer from allergy at some point in their lifetime. Moreover, the problem is not going to disappear because new allergies are being reported. So far, there has been disappointingly little progress with regard to treating allergies. Allergic reactions arise from an over-zealous immune system, with mast cells playing a particularly important role. Mast cells can be activated by harmless stimuli, such as pollen or animal fur, and this leads to an exaggerated response, which includes the excessive release of chemicals which affect the airways, blood vessels and stimulate other immune cells resulting in a chronic inflammation. Mast cells activate when tiny pores (channels) in their surface open, letting calcium ions flood into the cell. Controlling these pores is therefore a very effective way to manage mast cells. We have recently identified new mechanisms that control calcium entry and established how the incoming calcium activates mast cell responses. More importantly, we have developed a new strategy for manipulating mast cell activity and which could be useful in treating nasal polyposis, an inflammatory response in the upper airways sustained by mast cells. We plan systematic studies to dissect out the molecular pathways that control the calcium channel in healthy mast cells and how these processes are altered in human disease (polyposis and dermatitis). We will also test our new therapeutic strategy for controlling mast cell activation, using a novel system we have developed that is relevant to the real disease situation.
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