Salivary gland function is important in maintaining normal oral health, as well as playing a critical role in proper digestion. Normal salivary gland function and homeostasis is dependent upon the balance of cell growth, maintenance of cellular differentiation and cell death. Several million people in the United States suffer from benign and malignant tumors of the major and minor salivary glands and salivary gland hypofunction. Salivary gland hypofunction can be caused by chronic drug treatment, particularly in the elderly, Sjorgen's syndrome, an autoimmune disease, X-ray irradiation and cancer chemotherapy. In each of these disease conditions, salivary gland function may be compromised by the loss of the acinar cells or loss of glandular homeostasis due to aberrant apoptosis. The long range goal of this Program Project is to provide the fundamental information that is necessary to fully understand salivary acinar apoptosis at the molecular level. The development of such basic scientific information is essential in understanding the molecular basis of salivary gland tumor development and for the development of new therapeutic modalities for the treatment of prevention of salivary gland hypofunction caused by aberrant apoptosis. Project One will evaluate the role of the caspase and Bcl-2 superfamilies in salivary acinar apoptosis. Project Two will evaluate the role of the MAPK and Akt signal transduction pathways in regulating acinar apoptosis. Project Three will investigate the role of the protein kinase C family of regulatory proteins in suppressing and/or enhancing genotoxic agents and the onset of apoptosis. A fundamental understanding of how important intracellular signal transduction pathways along with the initiators and effectors of salivary acinar apoptosis is the first step in the development of new therapeutic strategies for the treatment of salivary gland hypofunction in neoplastic development.