Taste dysfunction, either loss or alteration in sensation, is a common occurrence during radiotherapy for head and neck cancer. In addition to anti-tumor effects, however, ionizing irradiation frequently causes significant side effects in the surrounding oral mucosa (blistering/mucositis) and salivary glands (dry mouth/xerostomia). Although protocols have been developed to minimize some oral sequelae, mitigation of the impact of irradiation on taste function has remained elusive. Importantly, patients with reduced taste sensation tend to lack appetite and eat far less, leading to weight loss, as well as a significantly compromised quality of life. While radiotherapy induced taste loss is a well-documented side effect of cancer treatment, the precise target(s) responsible have not been determined. Plausible explanations have been put forth, including indirect effects, i.e., reduced salivation and oral blistering, and direct mechanisms such as disruption of taste bud innervation, loss of particular taste receptor cell type(s), as well as loss of taste progenitor cells. Our preliminary data favor the hypothesis that proliferating taste bud progenitor cells are the direct targets of radiation damage. Accordingly, in Aim 1 of this proposal, we will determine the kinetics of taste cell renewal by taste bud progenitors, and examine how irradiation affects this actively cycling progenitor population. We will also define the contribution of radiation-induced cell cycle arrest, DNA repair and apoptosis to taste cell renewal following injury. In Aim 2 we will investigate the role of the novel protein kinase C delta isoform (PKC4) in irradiation-induced taste epithelial injury. PKC4 is a key regulator of irradiation-induced apoptosis, i.e., suppression of PKC4 protects irradiated salivary gland cells from death. PKC4 has also been implicated in maintenance of cell cycle arrest required for DNA repair in UV damaged human keratinocytes. Thus, we will test the hypothesis that loss of PKC4 protects taste progenitor cells from death, and/or promotes their continued mitosis following irradiation injury. This model is suggested by our preliminary data, which indicate that, while PKC4 KO mice possess normal taste epithelia, in response to irradiation, their taste bud progenitor cell population appears to be protected and continues to proliferate. In sum, our taste model, where progenitors and differentiated taste receptor cells are distinct and readily identifiable, will allow us to better understand the precise cell population(s) targeted by head and neck radiation. Further, the defined cellular organization of taste epithelium will allow us to tease apart the functions of PKC4 in taste epithelium, and lead potentially to development of specific pharmacological inhibitors of PKC4 to protect oral tissues from irradiation-induced damage. PUBLIC HEALTH RELEVANCE: Radiation therapy of head and neck cancer frequently causes damage to nearby tissues in the oral cavity. In particular the majority of patients will experience an altered or reduced sense of taste, resulting in loss of appetite, weight loss, and a significantly compromised quality of life. Studies in this proposal will address novel and important questions regarding the cellular and molecular basis of taste loss in patients treated with irradiation for head and neck cancer. Understanding how taste loss occurs will enable the development of therapeutic strategies to reverse or prevent taste loss and improve the quality of life of patients undergoing head and neck irradiation.