Water homeostasis is central to numerous aspects of normal lung function and pathophysiology, however the molecular mechanisms regulating water movement in the lung are incompletely defined. Aquaporins (AQP) are water specific membrane channel proteins that have been shown to be rate-limiting for water transport in numerous cell and animal models. Examples of AQP-related pathophysiology in humans are also emerging. Four AQPs are present in the respiratory tract: AQP1 in vascular endothelium; AQP3 in basal cells of airway and nasopharyngeal epithelium; AQP4 in the basolateral membrane of columnar cells in the airway epithelium; and AQP5 in the apical membrane of submucosal glands and type I pneumocytes. Regulation of these proteins is complex, and occurs at multiple levels. This proposal focuses on regulation of expression of AQP1 and AQP5, both of which are likely to participate in regulation of water movement in the airways and in the distal lung.
Aim I focuses on the effect of post-translational modifications of AQP1 and AQP5 on protein abundance. Sites of AQP1 or AQP5 ubiquitination will be determined by making mutations of lysine residues in each protein. The effect of ubiquitination on protein stability will be determined using these mutated molecules. Phosphorylation of AQP1 and AQP5 will also be examined, and a potential relation between phosphorylation and ubiquitination explored.
Aim II focuses on signaling mechanisms which regulate AQP1 and AQP5 expression in cell culture models, in particular the role of receptor tyrosine kinases in induction of these proteins. These studies should provide insight into mechanisms regulating expression of AQP1 and AQP5, and establish a framework from which to better understand their role in the pathophysiology of the respiratory tract.
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