Sjogren's syndrome (SS) is an autoimmune disorder characterized by inflammation and destruction of lacrimal and salivary glands leading to xerostomia. The diminished function of exocrine glands in SS is often associated with lymphocytic infiltration of the tissue and increased production of pro- inflammatory cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma). We have shown that the G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is up-regulated in response to damage or stress in salivary gland epithelium. The role of the P2Y2R in stressed salivary epithelium has not been determined, however, studies in our lab have shown that in vascular endothelium the activation of up-regulated P2Y2Rs increases the expression of VCAM-1 and promotes the binding and transendothelial migration of monocytes. Preliminary results indicate that activation of P2Y2Rs in salivary epithelium up-regulates VCAM-1 expression and stimulates lymphocyte adherence, a source of cytokine release. Moreover, we have obtained evidence that P2Y2R activation in salivary glands enhances activity of metalloproteases that are involved in the release of soluble cytokines from the salivary epithelium. These data strongly support a hypothesis that P2Y2R expression and activation in salivary gland cells contributes to epithelial dysfunction in SS by regulating the expression of adhesion molecules that promote the binding of immune cells to salivary epithelium and by activating metalloproteases involved in the release of cytokines that compromise epithelial integrity. Therefore, proposed studies will utilize polarized rat parotid (Par-C10) monolayers to evaluate the role of P2Y2Rs in the expression of specific adhesion molecules that promote lymphocyte adherence (Specific Aim 1) and to the activation of metalloproteases that generate pro-inflammatory cytokines (Specific Aim 2). Then, the effects of relevant cytokines will be evaluated with respect to transepithelial anion secretion (l(sc)) and the expression and phosphorylation of epithelial cell tight junction proteins that regulate ion transport and epithelial integrity in salivary glands (Specific Aim 3). These studies may lead to better therapeutic strategies for minimizing autoimmune-associated dysfunction of salivary gland that contributes to xerostomia in patients with SS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DE017633-03
Application #
7429729
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Hardwick, Kevin S
Project Start
2006-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$91,149
Indirect Cost
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Baker, Olga J (2010) Tight junctions in salivary epithelium. J Biomed Biotechnol 2010:278948
Baker, Olga J; Schulz, David J; Camden, Jean M et al. (2010) Rat parotid gland cell differentiation in three-dimensional culture. Tissue Eng Part C Methods 16:1135-44
Perry, Clint; Baker, Olga J; Reyland, Mary E et al. (2009) PKC{alpha}{beta}{gamma}- and PKC{delta}-dependent endocytosis of NBCe1-A and NBCe1-B in salivary parotid acinar cells. Am J Physiol Cell Physiol 297:C1409-23
Baker, Olga J; Camden, Jean M; Redman, Robert S et al. (2008) Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line. Am J Physiol Cell Physiol 295:C1191-201
Baker, Olga J; Camden, Jean M; Rome, Danny E et al. (2008) P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line. Mol Immunol 45:65-75