The chief goal is to understand how the hormone vasopressin regulates water excretion by the kidney. Vasopressins action is mediated through regulation of the molecular water channel aquaporin-2. Based on our studies a decade ago, it is now clear that vasopressin regulates aquaporin-2 in a time frame of seconds to minutes by altering the distribution of the water channel aquaporin-2 between the plasma membrane and the cytoplasm via vesicular trafficking. Trafficking of aquaporin-2 to the plasma membrane renders the cells permeable to water. We are presently using a systems approach to address the mechanisms involved. For this approach, we are integrating protein mass spectrometry, DNA microarrays, mathematical modeling and physiological methods. The following is a summary of work over the past year appearing in the 32 references published in 2006 and so far in 2007. ? The first 8 references in the reference list below show publications that have used protein mass spectrometry (1-8) to investigate protein networks involved in regulation of renal water and solute transport. The next four references (9-12) are clinically-oriented papers which describe bioengineering work to exploit our recent discovery that normal kidneys excrete exosomes in the urine. Exosomes are are small membrane particles secreted by every cell type facing the urinary space in the kidney. The goal of these studies is to develop the methods infrastructure to allow clinical investigators to isolate urinary exosomes for disease biomarker studies (9-12). The next 11 references describe work focusing on the use of animal models of disease processes to discover the pathophysiological basis of salt and water imbalance disorders (13-23). The disorders under investigation are nephrogenic diabetes insipidus, urinary tract obscruction, hepatic cirrhosis, congestive heart failure, gentamicin-induced nephrotoxicity, and hypertension. These studies, using methods developed in our laboratory in the 1990s, are done in a collaboration with former post-doctoral fellow Soren Nielsen. The next two papers (24,25) report similar studies on blood pressure regulation done with two other collaborators and former laboratory members, Susan Wall of Emory University and Randall Packer of George Washington University. The final seven papers address how the kidney concentrates solutes in the urine, making heavy use of transgenic and knockout mice(26-32).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL001285-21
Application #
7594384
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2007
Total Cost
$2,161,645
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Saethang, Thammakorn; Hodge, Kenneth; Kimkong, Ingorn et al. (2018) AbDesigner3D: a structure-guided tool for peptide-based antibody production. Bioinformatics 34:2158-2160
LeMaire, Sophia M; Raghuram, Viswanathan; Grady, Cameron R et al. (2017) Serine/threonine phosphatases and aquaporin-2 regulation in renal collecting duct. Am J Physiol Renal Physiol 312:F84-F95
Cheng, Lei; Pisitkun, Trairak; Knepper, Mark A et al. (2016) Peptide Labeling Using Isobaric Tagging Reagents for Quantitative Phosphoproteomics. Methods Mol Biol 1355:53-70
Sandoval, Pablo C; Claxton, J'Neka S; Lee, Jae Wook et al. (2016) Systems-level analysis reveals selective regulation of Aqp2 gene expression by vasopressin. Sci Rep 6:34863
Sanghi, Akshay; Zaringhalam, Matthew; Corcoran, Callan C et al. (2014) A knowledge base of vasopressin actions in the kidney. Am J Physiol Renal Physiol 307:F747-55
Bradford, Davis; Raghuram, Viswanathan; Wilson, Justin L L et al. (2014) Use of LC-MS/MS and Bayes' theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser256. Am J Physiol Cell Physiol 307:C123-39
Knepper, Mark A; Raghuram, Viswanathan; Bradford, Davis et al. (2014) Letter to the editor: ""Systems biology versus reductionism in cell physiology"". Am J Physiol Cell Physiol 307:C308-9
Hoffert, Jason D; Pisitkun, Trairak; Saeed, Fahad et al. (2014) Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct. Am J Physiol Renal Physiol 306:410-21
Trepiccione, Francesco; Pisitkun, Trairak; Hoffert, Jason D et al. (2014) Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2. Kidney Int 86:757-67
Saeed, Fahad; Hoffert, Jason D; Knepper, Mark A (2014) CAMS-RS: Clustering Algorithm for Large-Scale Mass Spectrometry Data Using Restricted Search Space and Intelligent Random Sampling. IEEE/ACM Trans Comput Biol Bioinform 11:128-41

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