The long term objective of this application is to gain insight into the cellular and molecular controls of lacrimal secretion. The intent of the work is to provide a framework for understanding the pathogenesis of Sjogren's syndrome (SS) and for the development of therapies for dry-eye associated with the disease.
The specific aims of this application are designed to test three hypotheses that address 1) the relationship between early changes in the lacrimal gland and the later onset of autoimmune disease and 2) the identification of the cellular and molecular mechanisms that underlie the influence of the hormonal environment on the development and treatment of SS. The first specific aim will test the hypothesis that alterations in the expression or activity of G-protein coupled receptor (GPCR) signaling molecules occur prior to lymphocytic infiltration and result in disruptions in secretion that contribute to the lacrimal insufficiency of SS. Physiologic secretory function, cell-surface receptor-G protein coupling and mRNA and protein expression of G protein subunits, and relevant isoforms of adenylyl cyclase, phospholipase C and protein kinases will be evaluated in pre-autoimmune genetic models of SS and in control animals. The second specific aim will test the hypothesis that the autoimmune response in SS is, in part, precipitated by inappropriate Fas/Fas L mediated apoptosis of epithelial cells of the lacrimal gland.
The second aim will also test the hypothesis that the occurrence of apoptosis is influenced by the altered expression or activity of key GPCR signaling molecules.
The second aim will be accomplished by the evaluation of apoptosis in lacrimal epithelial cells of genetic models of SS prior to lymphocytic infiltration. The effect of activation or inhibition of GPCR signaling molecules on the occurrence of apoptotic figures and on the mRNA and protein expression of Fas, Fas L and bcl-2 family members will be measured. Alteration of the phosphorylation state of bcl-2 family members by these treatments will also be assessed. The final specific aim will test the hypothesis that the mechanism by which androgens maintain or restore lacrimal function is by influencing the expression or function of GPCR and/or programmed cell death signaling molecules. This will be tested by acute and chronic exposure of lacrimal acinar cells to androgen. Genomic and non-genomic effects of androgen on secretory function and on the expression and activity of signaling molecules will be assessed by similar methods used to accomplish the first and second specific aims.
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