PhD defence H. (Haoxiao) Zuo

Compartmentalized cAMP Signaling in COPD Focus on Phosphodiesterases and A-Kinase Anchoring Proteins

Cyclic AMP (cAMP) is one of the most effective therapeutic targets in various pulmonary diseases and plays a vital role in relaxing airway smooth muscles and suppressing airway inflammation. However, tolerance in the long-term use and side-effects create the need of more effective approaches. cAMP is able to modulate signaling cascades in a spatio-temporal manner. Therefore, comprehensive understanding of the fluctuations (generation and degradation) of cAMP and its potential functions within certain compartments will most likely help in the screening of novel pharmaceutical targets which have higher efficiency and fewer side effects. In this thesis, Haoxiao Zuo investigated the role of compartmentalized cAMP signaling in a number of structural airway cells of relevance to cigarette smoke exposure using classic pharmacological methods and novel fluorescent tools. Special focus was on phosphodiesterases (PDEs) and A-kinase anchoring proteins (AKAPs). The author found that the expression (mRNA and protein) and activity of both PDE3 and PDE4 were upregulated by cigarette smoke exposure, which likely underpinned alterations of intracellular cAMP levels. In addition, other PDE member, such as PDE8, was a novel target which needed more investigation in the future. In the last part of her thesis, the author showed that AKAPs, with specific focus on Ezrin, Yotiao and AKAP95, played a vital role in maintaining TGF-β1/ cigarette smoke-induced Epithelial-to-mesenchymal transition. Therefore, compartmentalized cAMP signaling being modulated by PDEs and AKAPs represents a promising target to treat airway disorders.

Promotores: Prof.dr. M. Schmidt