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Languages: English
Types: Doctoral thesis
Subjects: QH301
In the adult, changes in free ionized plasma calcium concentration (Ca2+ G) are monitored by the G-protein-coupled, extracellular calcium-sensing receptor, CaR, but whether CaR plays a role in lung development is unknown. CaR has the potential to be a key regulator of Ca2+ dependent cell fate during development. It is hypothesized that extracellular calcium is an important extrinsic factor that modulates the intrinsic lung developmental programme, through activation of the CaR. CaR is expressed in the developing mouse lung in the pseudoglandular phase, from embryonic day 10.5 (El0.5), with a peak of expression at El2.5 and a subsequent decrease by El8, after which the receptor is absent. Lung branching morphogenesis in vitro is sensitive to Ca2+ G, being negatively modulated by the higher, fetal (i.e., 1.7 mM) Ca2+ 0 yet optimal at physiological adult Ca2+ Q (i.e., 1.05-1.2 mM). Administration of the specific CaR positive allosteric modulator, the calcimimetic R-568, mimics the suppressive effects of high Ca2+G on branching morphogenesis while both phospholipase C and PI3 kinase inhibition reverse these effects. CaR activation suppresses cell proliferation while it enhances lung distension, fluid secretion and intracellular calcium signalling. Conditions which are restrictive to branching and fluid secretion can be rescued by manipulating Ca2+ 0 in the culture medium. Lung explant cultures from the current mouse model of CaR inactivation respond in a similar manner to Ca2+ Q and the calcimimetic R-568. These results indicate the presence of expression of a functional CaR splice variant, which is detected at El 1.5, 12.5 and 15.5 in CaR knockout lungs. The observations presented here support a novel role for the CaR in preventing hyperplastic lung disease in utero and present two potential models for its mode of action within this system.
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