Dry mouth is one of the major complications of Sj?gren's Syndrome (SS), a chronic autoimmune disorder mainly affecting the exocrine glands. The current therapies for treating dry mouth in SS are predominantly directed towards providing symptomatic relief. Clearly, therapeutic regimens capable of suppressing an ongoing autoimmune response coupled with restoration of salivary gland function will be critical for providing long term relief. The major goal of this application is to evaluate adenosine receptor (AR) agonists as candidate drugs for restoring salivary gland function in a spontaneous mouse model for SS. Adenosine, a major anti-inflammatory metabolite, signals through four G protein coupled receptors termed A1AR, A2aAR, A2bAR and A3AR. This application will test the hypothesis that AR agonists, particularly those targeting the A2aAR and A2bAR, will restore salivary gland function in SS by suppressing an ongoing autoimmune response as well as by directly affecting the salivary gland function. The hypothesis will be investigated in a spontaneous mouse model for SS. Female mice with fully developed symptoms of SS will be treated with AR agonists and restoration of salivary gland function monitored by measuring pilocarpine induced salivation. Systemic immunosuppressive effects of AR agonists will be monitored by measuring autoantibody responses and serum cytokine levels. Localized immunosuppression within the salivary glands will be studied by analyzing gene expression levels of different pro-inflammatory cytokines within the submandibular glands and degree of sialoadenitis. To determine direct effects of AR agonists on salivary glands, Ca2+ mobilization and phosphorylation of ERK1/2 in submandibular gland acini will be monitored. Several adenosine receptor agonists have either completed or are currently undergoing human clinical trials for different indications. The successful completion of this application will provide a majo impetus for advancing these drugs to human clinical trials for restoration of salivary gland function in SS. This application is closely aligned and highly significant for the missions of NIDCR and the improvement of oral health.

Public Health Relevance

This application will test the ability of drugs targeting a certain class of receptors called the adenosine receptors for restoring salivary gland function in a mouse model for Sj?gren's syndrome. Successful completion of this application will pave the way for future human clinical trials for treating dry mouth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21DE022977-02
Application #
8508243
Study Section
Special Emphasis Panel (ZDE1-MH (14))
Program Officer
Burgoon, Penny W
Project Start
2012-07-10
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$193,536
Indirect Cost
$78,336
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Bagavant, H; Nandula, S R; Kaplonek, P et al. (2014) Alum, an aluminum-based adjuvant, induces Sjögren's syndrome-like disorder in mice. Clin Exp Rheumatol 32:251-5
Nackiewicz, Dominika; Dey, Paromita; Szczerba, Barbara et al. (2014) Inhibitor of differentiation 3, a transcription factor, regulates hyperlipidemia-associated kidney disease. Nephron Exp Nephrol 126:141-7
Szczerba, B M; Rybakowska, P D; Dey, P et al. (2013) Type I interferon receptor deficiency prevents murine Sjogren's syndrome. J Dent Res 92:444-9
Deshmukh, Umesh S; Bagavant, Harini (2013) When killers become helpers. Sci Transl Med 5:195fs29