The functions of the human vascular system, lung and kidney are critically dependent on epithelial and endothelial cells forming tubes of the correct diameters and lengths. However, the mechanisms controlling long-term tube size are poorly understood. This lack of understanding is reflected in the lack of effective treatments for many human diseases in which tube-size control is defective, such as polycystic kidney disease and vascular malformations, and our inability to control tube size to treat diseases not directly due to tube-size defects. For example, drugs that increase vascular tube diameter could potentially be used to treat ischemia, while drugs that block vascular tube size increases could be used as anti-angiogenic drugs to block solid tumor growth. The Drosophila tracheal system, a ramifying network of epithelial tubes that functions as a combined pulmonary/vascular system, provides an excellent system for using molecular genetic approaches to investigate the basic mechanisms of tube-size control. Preliminary work shows that the NaK ATPase 13subunit nrv2 is specifically required for tracheal tube-size control and for assembling septate junctions, the Drosophila equivalent of vertebrate tight junctions. The human NaK ATPase is mislocalized in polycystic kidney disease (PKD), which affects 1 in 800 people and is characterized by abnormal tube enlargement. It is unclear whether NaK ATPase mislocalization is part of the cause of, or the result of, PKD, but the preliminary studies suggest that a previously unidentified cell junctional function of the NaK ATPase could play a critical role in controlling tube size in the kidney and other tubular organs. The first specific aim of this proposal will be to investigate the role of septate junction complexes in tube-size control by determining whether several of their components act cell-autonomously and whether a known cell polarity function of several septate junction components mediates tracheal tube-size control.
The second aim i s to perform detailed molecular and genetic investigations of the roles of the nrv2 NaK ATPase and two Drosophila claudins, sinuous and megatrachea in tracheal tube-size control.
The third aim i s to clone and begin analyzing another gene that appears to define a distinct class of tube-size control gene than currently analyzed genes. ? ? ?
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