Vasopressin (VP) is the major antidiuretic hormone involved in the regulation of water reabsorption by mammalian kidney. Intensive studies have established that VP functions by recruiting the AQP2 water channel from cytoplasmic vesicles to the plasma membrane of collecting duct principal cells. The impairment of VP-AQP2 signaling pathways results in diabetes insipidus as well as fluid retention seen in some heart failure patients. AQP2 is regulated through complex trafficking pathways. Our hypothesis is that regulated trafficking of AQP2 requires direct and indirect protein-protein interactions during intracellular translocation, exocytosis as well as endocytosis. The proposed studies are divided into three specific aims addressing identification and characterization of novel AQP2 interacting proteins as well as investigation of the functional significance of these novel protein interactions on AQP2 trafficking in vitro and in vivo. The proposed study will utilize multidisciplinary approaches (molecular biology, cell biology, biochemistry and immunocytochemistry) and powerful technology (yeast two hybrid screen, structural functional analysis, gene transfer) to identify and characterize novel protein-protein interactions and their biologic functions. These studies will provide important information of the poorly understood molecular mechanisms underlying AQP2 trafficking, and may ultimately lead to better therapies for patients with defective urinary concentration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK065417-01
Application #
6693218
Study Section
Special Emphasis Panel (ZRG1-F10 (21))
Program Officer
Rankin, Tracy L
Project Start
2003-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$53,944
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lu, Hua; Sun, Tian-Xiao; Bouley, Richard et al. (2004) Inhibition of endocytosis causes phosphorylation (S256)-independent plasma membrane accumulation of AQP2. Am J Physiol Renal Physiol 286:F233-43