The quality of life for millions of Americans is adversely affected by salivary gland hypofunction caused by a variety of etiologies including systemic diseases, radiation therapy, xerogenic medications, and Sj6gren's syndrome. The development of interventions to restore function for these individuals requires a thorough understanding of the molecular physiology of salivary glands. Salivary secretion involves a two-step process: acinar cells initially secrete an isotonic, plasma-like fluid;duct cells subsequently modify this primary secretion to conserve NaC1. Both the fluid secretion and NaC1 reabsorption processes are dependent upon the coordinated action of multiple Na+ transport mechanisms including Na+/H+ exchangers, Na+ channels, and Na+/K+/2C1- co-transporters. Genetically modified mice have proven to be valuable models of human salivary gland dysfunction, and are useful for confirming the molecular identities and the functional properties of important Na+ transporters. Nevertheless, significant gaps remain in our understanding of the function of the major Na+ transporting proteins. To address remaining questions, we propose a molecular and functional comparison of Na+ transporter physiology in human and mouse salivary glands. We will test the overall hypothesis that Na+ transport proteins are critical to saliva formation. Specifically:
Aim 1) will take advantage of genetically modified mice generated by targeted disruption of the Na+ channel ENaC (Scrmla) and the Na+/H+ exchanger Nhe4 [Slc9a4) genes to directly test whether these Na+ transport proteins are essential for salivary gland secretion;
Aim 2) will assess whether agonists that mobilize intracellular Ca 2+, or increase the intracellular cAMP content, acutely regulate the activity of the different Na+ transport mechanisms in human and mouse salivary cells;
and Aim 8) will determine whether gene disruption affects saliva production through systemic or gland-specific mechanisms. Ultimately, the information gained from these Aims will aid in the development of therapies to remedy various forms of salivary gland dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE008921-24
Application #
8474741
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
1989-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
24
Fiscal Year
2013
Total Cost
$382,163
Indirect Cost
$99,341
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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