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 ?-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. Our long-term goal is to understand how protein kinase C delta (PKC?) regulates the response of the salivary gland to IR, so as to develop better strategies for radioprotection. Our previous studies show that inhibition of PKC? 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 PKC? regulates DNA damage induced apoptosis, and conversely, how inhibition of PKC? provides radioprotection. Our studies in Aim 2 of the parent grant address the hypothesis that PKC? decreases apoptosis/increases survival (i.e., provides salivary gland radioprotection) by increasing DNA repair. Based on our preliminary data toward this Aim, we are requesting a collaborative supplement to explore a previously unknown role for PKC? in chromatin remodeling. We propose to collaborate with Dr. Black, an expert in chromatin biology at our institution, to ask if regulation of DNA repair by PKC? is mediated through changes in chromatin structure, and identify chromatin regulatory enzymes required for PKC?-dependent changes in DNA repair and chromatin structure. Our proposed collaboration with Dr. Black is essential as this expertise is not available in my laboratory. These studies may directly link a PKC?- regulated chromatin regulating enzyme with radioprotection. Future studies will determine if regulators of chromatin remodeling can be used for radioprotection of the salivary gland in vivo.
Treatment of head and neck cancer typically involves surgery followed by fractionated radiation therapy. Although attempts are made to limit radiation exposure to normal tissues, many patients suffer moderate to severe collateral damage to the salivary glands, resulting in loss of saliva, chronic oral infections and severe discomfort. There is a great need for safe and efficient therapeutic interventions for protection of the salivary gland and other oral tissues in this vulnerable patient population. Our studies will define the mechanism(s) underlying radioprotection of the salivary gland by inhibition of PKC? and TKIs, and may lead to the identification of new ?rational? strategies for radioprotection for oral tissues.
