) Regulated movement of water in the lung is essential for normal lung function. After years of characterizing lung water dynamics on a gross scale, recent exploration of cellular and subcellular factors contributing to water transport has yielded additional insight into this process. This proposal is an extension of the applicants interest in basic lung biology, specifically, mechanisms of lung water homeostasis. This interest began with studies of acute lung injury and pulmonary hemodynamics in medical school, continued through clinical training in internal medicine, and most recently is being pursued through the study of aquaporin (AQP) water channel proteins. Aquaporins are water specific transmembrane channels, originally identified in red blood cells and renal proximal tubule, but recently shown to have complex ontogeny and distribution in the lung. Distinct nonoverlapping expression of different homologs throughout the respiratory tract suggests a number of potential functions, but also predicts complex regulation. In particular, preliminary studies demonstrate that Aqp1, abundantly expressed in visceral pleura, bronchial circulation, and nasopharyngeal vessels of the rat, can be induced in vitro and in vivo by a variety of physiologically relevant agents. This proposal builds on previous observations made by the applicant, focusing on the molecular and cellular regulation of Aqp1 in models relevant to lung physiology. Three principal lines of inquiry are to be undertaken: I) molecular genetic analysis of the Aqp1 promoter in mouse; II) in vitro characterization of molecular mechanisms regulating aqp1 expression in response to corticosteroids, hypoxia, and hyperosmalarity; and III) generation of Aqp1 null transgenic mice for subsequent characterization of the phenotype. The proposed studies are to be carried out at Johns Hopkins under the mentorship of Dr. Peter Agre, who discovered water channel proteins and continues to lead the field in their investigation. The environment at Johns Hopkins greatly facilitates this type of investigation, as both support and stimulation are abundantly present. The candidate has recently worked in Dr. Agre's laboratory but now wishes to undertake a distinctly different line of investigation, a molecular genetic approach to regulation of Aqp1 expression. These studies should enhance the understanding of the molecular mechanisms regulating lung water homeostasis.
| Leitch, V; Agre, P; King, L S (2001) Altered ubiquitination and stability of aquaporin-1 in hypertonic stress. Proc Natl Acad Sci U S A 98:2894-8 |
