The lungs’ immune system relies on a constant conversation between the cells lining the airways and the resident immune cells that patrol them, and this project will map the molecular signals that keep that conversation from turning into an allergic attack. When this signalling network breaks down—due to genetic quirks, early-life infections, or ageing—the lungs can mount an immune response to harmless particles like pollen or dust mites, triggering asthma. Current treatments manage symptoms but do not fix the underlying miscommunication. This research aims to identify exactly which molecular pathways (especially those involving TGFbeta and IL-10) are disrupted, and how those disruptions alter the behaviour of alveolar macrophages and epithelial cells. The team will use mouse models and cells from children and adults with severe asthma to compare healthy and diseased signalling. If successful, the work will reveal new targets for drugs that restore normal immune tolerance in the lungs, rather than just suppressing inflammation. This is fundamental science—it will not produce a therapy tomorrow—but understanding these cellular interactions is a necessary step toward treatments that could prevent asthma from developing or progressing, particularly in children.
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This application will test the hypothesis that interaction between pulmonary epithelial cells and alveolar macrophages is vital for maintenance of immune homeostasis within the respiratory tract. Disruption of this network, either genetically via abnormal expression of particular genes, concomitant with environmental influences, such as age or infection, alters the threshold for immune responses to occur to usually innocuous particles resulting in pulmonary allergic inflammation. The programme i s designed to gain insight into the phenotypic and functional characteristics of alveolar macrophages (AM) and determine how they interact with pulmonary epithelial cells. We will investigate the molecular pathways that define these interactions, focusing particularly on TGFbeta and IL-10, in order to determine how they influence allergic immunity, and image their communications within the lung. Furthermore, we will determine how interactions are affected by expression of genes identified from a sthma GWAS particularly during early life. In concert we will examine the characteristics of AM from the human respiratory tract by collecting cells from adults and children with severe asthma. These aims will be approached concurrently using a range of well-characterised in vivo mouse models and in vitro cell culture systems established with cells from asthmatic adults and children. In order to facilitate our understanding of disease pathogenesis knowledge of key molecular and cellular interac tions is vital. Ultimately this programme will further our understanding of the cellular and molecular interactions that operate within the pulmonary tract at homeostasis and during allergic disease and will identify novel pathways for therapeutic intervention.
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