The central focus of this proposal is to define the basic mechanisms of water/fluid transport in the lung and airways in health and disease, and to identify new targets for drug development. Aquaporins (AQPs) are water-transporting proteins expressed in lung microvasculature (AQP1), airways (AQP3 and AQP4), alveolar epithelium (AQP5) and submucosal gland epithelium (AQP5). In the initial award period, mice lacking each of the four major lung aquaporin water channels were generated and used to study the role of aquaporins in fluid transport in alveoli, large airways, and airway submucosal glands. An important finding - AQP5-dependent fluid secretion in airway submucosal glands - will be followed up in Aim 1. Novel aquaporin-selective inhibitors and model systems will be used to test the hypothesis that fluid secretion in human submucosal glands is regulated by AQP5 expression and function.
Aim 2 will critically address the role of aquaporins in other aspects of lung physiology using inhibitors, mouse models, and human tissues. The hypothesis will be tested that lung/airway aquaporins facilitate fluid removal from the airspaces and lung parenchyma following clinically relevant disease/injury.
In Aim 3, novel lung slice, cell culture and fluorescence methods will be used to define water and salt transporting mechanisms in distal airways, an important but under-studied epithelium. The hypothesis that AQP4 and CFTR are required for distal airway fluid absorption will be tested, and the role of the distal airway epithelium is lung fluid clearance will be determined. Together, these experiments will provide definitive information on the role of aquaporins in lung physiology and disease. A unique strength of our research program has been the introduction of new approaches to study lung physiology in vivo and in freshly harvested tissues, and the development of incisive biophysical tools (fluorescent probes, microscopy methods) and inhibitors for water and ion transport studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059198-08
Application #
7101073
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
1998-09-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
8
Fiscal Year
2006
Total Cost
$332,864
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Verkman, A S (2013) Aquaporins. Curr Biol 23:R52-5
Verkman, Alan S; Ratelade, Julien; Rossi, Andrea et al. (2011) Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica. Acta Pharmacol Sin 32:702-10
Crane, J M; Tajima, M; Verkman, A S (2010) Live-cell imaging of aquaporin-4 diffusion and interactions in orthogonal arrays of particles. Neuroscience 168:892-902
Tradtrantip, Lukmanee; Yangthara, Buranee; Padmawar, Prashant et al. (2009) Thiophenecarboxylate suppressor of cyclic nucleotides discovered in a small-molecule screen blocks toxin-induced intestinal fluid secretion. Mol Pharmacol 75:134-42
Li, Lihua; Zhang, Hua; Ma, Tonghui et al. (2009) Very high aquaporin-1 facilitated water permeability in mouse gallbladder. Am J Physiol Gastrointest Liver Physiol 296:G816-22
Li, Lihua; Zhang, Hua; Verkman, A S (2009) Greatly attenuated experimental autoimmune encephalomyelitis in aquaporin-4 knockout mice. BMC Neurosci 10:94
Tradtrantip, Lukmanee; Tajima, Masato; Li, Lihua et al. (2009) Aquaporin water channels in transepithelial fluid transport. J Med Invest 56 Suppl:179-84
Ruiz-Ederra, Javier; Verkman, A S (2009) Aquaporin-1-facilitated keratocyte migration in cell culture and in vivo corneal wound healing models. Exp Eye Res 89:159-65
Magzoub, Mazin; Zhang, Hua; Dix, James A et al. (2009) Extracellular space volume measured by two-color pulsed dye infusion with microfiberoptic fluorescence photodetection. Biophys J 96:2382-90
Haggie, Peter M; Verkman, A S (2009) Defective organellar acidification as a cause of cystic fibrosis lung disease: reexamination of a recurring hypothesis. Am J Physiol Lung Cell Mol Physiol 296:L859-67

Showing the most recent 10 out of 168 publications