Due to the location of the salivary glands in the oral cavity they are frequently an unintended target in patients treated with irradiation for head and neck cancer, resulting in permanent and often severe salivary gland hypofunction. Loss of saliva production can be debilitating as it affects digestion and chewing, and can result in increased chronic oral infections and diminished quality of life. Apoptosis of salivary epithelial cells, particularly acinar cells, is a major contributor to salivary gland damage and impaired secretory function in irradiated glands. We have shown that protein kinase C delta (PKC?) is required for apoptosis induced by ?- irradiation and other genotoxic agents in cultured parotid cells and in the parotid gland in vivo. The long-term goal of my lab is to understand how PKC? regulates apoptosis and to use this information to develop therapeutic strategies to suppress apoptosis in the salivary gland. Our work has defined how PKC? functions to regulate apoptosis in salivary cells, and has revealed a highly regulated pathway that controls nuclear import of PKC?, assuring that salivary acinar cells die only in response to specific damage signals. Importantly, we have identified critical steps in this process such as tyrosine phosphorylation of PKC? that can be targeted therapeutically. As tyrosine phosphorylation initiates pro-apoptotic signaling by PKC?, inhibiting the tyrosine kinases that mediate this step may suppress apoptosis in the salivary gland of patients undergoing head and neck irradiation. Here we will probe the mechanism by which the tyrosine kinases Src and c-Abl phosphorylate and activate PKC?, and explore the hypothesis that tyrosine kinase inhibitors can be used prophylactically to suppress apoptosis and loss of salivary gland function in response to irradiation. Our studies will also explore downstream targets of PKC? in the context of irradiation damage and address the hypothesis that PKC? regulates activation of the Extra-cellular-Regulated-Kinase (MEK/ERK) signaling pathway in the context of apoptosis. These later studies may identify additional therapeutic targets. As many tyrosine kinase and MEK inhibitors are FDA approved for cancer therapy; these classes of drugs could potentially be rapidly translated in to the clinic for use in patients receiving radiation therapy. Thus our studies may have a rapid and profound impact on the oral health and quality of life of the 45,000 patients diagnosed with head and neck cancer each year who face the prospect of loss of salivary gland function as a result of irradiation therapy.

R01DE015648

2003-12-01

2020-12-31