Transcriptional control of inflammatory gene expression in asthma. (360G-Wellcome-083122_Z_07_Z)

Recent work by our group and others suggests that airway smooth muscle (ASM) cells play a central role in chronic inflammation and airway remodelling in asthma by production of lipid mediators, chemokines, matrix metalloproteinases and growth factors. There is also evidence that airway smooth muscle (ASM) cells have intrinsic abnormalities in these synthetic pathways. Our preliminary studies show that ASM cells obtained from bronchial biopsies in asthmatic subjects produce more eotaxin, IL-8 and VEGF than cells from non-asthmatic subjects. We have shown that these genes are transcriptionally regulated in ASM cells by specific transcription factors and histone H4 acetylation and have started to identify the histone acetyl transferases responsible and the regulatory mechanisms involved. Furthermore we have found that histone acetyltransferase activity is increased in cells from asthmatic subjects. We will extend these studies to determine 1. which co-activator HATs stimulate inflam matory gene expression and how they and their co-repressor HDACs are regulated? 2. which aspects of transcriptional regulation are abnormal in asthma? 3. the effect of existing (beta-2 agonists and glucocorticoids) and novel (PPARgamma agonists, PKCbeta inhibitors) asthma therapies on these processes in normal and asthmatic cells. These studies will provide information regarding new therapeutic targets for chronic asthma.