Apoptosis, or programmed cell death, is an essential component of normal glandular development and homeostasis in all tissues of the body including salivary gland acinar cells. However, study of the molecular mechanism of apoptosis in salivary acinar cells has been hampered due to the lack of an in vitro cell model in which the expression of apoptosis-associated genes can be manipulated and their function evaluated. The highly differentiated parotid and submandibular salivary acinar cell lines have been developed. These cell lines will be used in this proposal to develop stable salivary acinar cell lines in which the expression of apoptosis-associated proteins can be regulated. These cell lines will be generated using the tetracycline (tet) regulated gene expression system. In this system cell lines are first made which express the tet transactivator protein (tTA). These cell lines are then secondarily transfected with a target gene which is under the control of a tTA regulated promoter. The level of expression of the target protein is regulated by the concentration of tet in the cell culture media. Th long term goal of this proposal is to utilize these model cell lines to determine the role of specific cellular modulators of apoptosis in salivary gland acinar cells. The first apoptosis-associated target gene to be examined is Bcl-2, a gene known to inhibit the entry of many cells into the apoptotic pathway. These cell lines will also have wide spread applications for the stud of many aspects of salivary acinar cell biology since they can be used for the regulated expression of virtually any target protein. Irradiation and drug-induced xerostomia, resulting in salivary acinar cell dysfunction, is a major oral health problem. A variety of mechanisms are likel to be involved, all of which have the potential of accelerating the salivary acinar cells into apoptosis, and thus enhancing glandular dysfunction and oral disease. A better understanding of salivary gland apoptosis and its regulation has the potential for the development of new treatment modalities to block or interfere with the toxic effects of these types of therapeutics and thus help to maintain or sustain normal salivary gland function.
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