ABSTRACT Over 50,000 people a year are diagnosed with head and neck cancer (HNC) in the US, the majority of whom will be treated with δ-irradiation (IR) therapy. Many of these patients will experience debilitating side effects as a consequence of IR damage to non-tumor tissues, including the oral mucosa, tongue and salivary glands. In particular, destruction of the salivary glands, and resultant hypofunction, is permanent and associated with chronic oral infections, caries, and severe discomfort. Early loss of salivary gland function is thought to result from direct damage to salivary acinar cells by IR and the subsequent loss of cells through apoptosis, while permanent loss of function likely results from the inability of the IR damaged gland to regenerate cells lost through apoptosis. Our long-term goal is to understand how protein kinase C delta (PKCδ) regulates the response of the salivary gland to IR, so as to develop better strategies for radioprotection. Our studies show that inhibition of PKCδ activation using tyrosine kinase inhibitors (TKIs) suppresses apoptosis and provides robust radioprotection in mouse models of head and neck IR. However, very little is known about the mechanisms by which PKCδ regulates DNA damage induced apoptosis, and conversely, how inhibition of PKCδ provides radioprotection. In Aims 1 and 2 of this proposal, we will explore the hypothesis that inhibition of PKCδ suppresses apoptosis and protects against the initial, or “early” effects of IR damage to the salivary gland through regulation of the DNA damage response and increased DNA repair. In addition to suppressing apoptosis, our preliminary data suggests that TKIs can provide long term radioprotection of salivary gland by promoting salivary acinar cell regeneration in vivo. In Aim 3 we will explore the hypothesis that TKIs promote regeneration of salivary acinar cells, and establish whether genetic disruption of PKCδ provides long term radioprotection though a similar mechanism. Our studies will define the mechanism(s) underlying radioprotection of the salivary gland by inhibition of PKCδ and TKIs, and may lead to the identification of new “rational” strategies for radioprotection for oral tissues. Although our focus is on the salivary gland, such strategies may also have implications for protection of other non-tumor tissues in patients undergoing IR and possibility chemotherapy, thus having a significant impact on the quality of life and efficacy of therapeutic interventions for a wide variety of cancer patients.