Programmed cell death (PCD) or apoptosis is a highly regulated physiological process which eliminates specific cells from an organism. PCD plays a critical role during embryonic development but is present throughout life. Unregulated or abnormal apoptosis can lead to disease or unwanted tissue destruction. Many tissues, including the salivary gland, express the surface molecule called Fas (CD95) which can deliver an apoptotic signal. Sjogren's syndrome is an autoimmune disease of the exocrine glands that leads to xerostomia and xeropthalmia. Many of the glandular features show evidence of apoptotic destruction. The long term objective of this study is to elucidate the mechanism leading to PCD in the Sj?rgren's syndrome salivary gland.
The Specific Aims are: 1) Study in situ Fas-mediated PCD, bcl-2 family protein expression, the affects of cytokines in the rat salivary gland; 2) Induce with cytokines Fas ligand and bcl-2 family protein expression in the salivary cell lines, (HSY, SMG C6 and SMG C10); 3) determine the role of proapoptotic caspases in rat and human salivary glands; 4) detect in the Sj?rgren's syndrome salivary gland abnormal changes in bcl-2 family member expression. Studies will include immunochemical staining techniques and Western blot Rat parotid and submandibular glands will be cannulated. Cytokines or ant-Fas antibody will be injected into the gland and assessed for apoptosis and PCD associated proteins. Salivary gland cell lines will be cultured with cytokines and studied for apoptosis, Fas-L expression, and bcl-2 family member expression. Gene transfer studies will be performed in vivo and in vitro to regulate Fas ligand and bcl-2 family prtein expression. Caspase inhibitors will be used to identify specific proteases during apoptosis. Biopsy material from patents with Sjogren's syndrome will be immunostained for bcl-2 family member expression.
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