Receptor tyrosine kinase regulation of mast cell-airway smooth muscle beta2-adrenoceptor function in asthma. (360G-Wellcome-094058_Z_10_Z)

£162,905

Beta2-adrenoceptor agonists form a cornerstone of asthma treatment by reversing and/or preventing bronchoconstriction. However, in some subjects beta2-adrenoceptor agonists are of poor efficacy, particularly during acute exacerbations, and regular use may lead to deterioration in asthma control. The mechanisms are poorly understood. Mast cell infiltration of the airway smooth muscle (ASM) in asthma is a characteristic feature of the asthmatic phenotype. Mast cells interact intimately with ASM th rough bi-directional cell-cell and mediator-dependent effects. Interestingly, human lung mast cell (HLMC) beta2-adrenoceptor responses are attenuated within minutes of exposure to stem cell factor due to beta2-adrenoceptor phosphorylation on Tyr350 and receptor internalisation. We hypothesise that mast cell-ASM cross-talk leads to beta2-adrenoceptor uncoupling in both cell types through receptor tyrosine kinase activity. If true, targeting these pathways may enhance beta2-agonist efficacy and sa fety in asthma. We will test this hypothesis by investigating: 1. The ability of HLMC and ASM-derived growth factors to phosphorylate and uncouple beta2-adrenoceptor agonist responses in these cells. 2. The ability of ASM in co-culture with HLMC to inhibit HLMC beta2-adrenoceptor agonist responses, and vice versa. 3. Expression of phosphorylated beta2-adrenoceptors in bronchial biopsies from subjects with asthma compared to healthy controls, and their correlation with clinical measurements .

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Grant Details

Amount Awarded 162905
Applicant Surname Amrani
Approval Committee Physiological Sciences Funding Committee
Award Date 2011-03-15T00:00:00+00:00
Financial Year 2010/11
Grant Programme: Title Project Grant
Internal ID 094058/Z/10/Z
Lead Applicant Dr Yassine Amrani
Other Applicant(s) Prof Chris Brightling, Prof Peter Bradding
Partnership Value 162905
Planned Dates: End Date 2014-12-31T00:00:00+00:00
Planned Dates: Start Date 2011-07-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East Midlands