Abstract:More than 73% of head and neck cancer patients continue to suffer from the chronic consequences ofxerostomia months to years after the completion of radiotherapy making this one of the most compellingissues in salivary gland biology. Despite technological advancements in cancer therapies collateraldamage to salivary glands remains a significant problem for these patients and severely diminishestheir quality of life. The field of radiation-induced salivary gland damage is severely hampered by thelack of a comprehensive model detailing the molecular stages of damage. The overall vision is torestore salivary gland function in patients following radiotherapy by identifying healing stages in salivaryglands that lead to the stratification and administration of precise therapeutics for their stage. Thisproposal will use the sequential phases of wound healing involving inflammation to its resolution andreconstitution of tissue through proliferation and differentiation of epithelial tissue as steps toaccomplish this vision. We hypothesize that irradiated salivary glands fail to efficiently progressthrough the wound healing phases leading to prolonged dysfunction. Our prior work has demonstratedthat radiation-induced proliferation in salivary glands is due in part to disruption of the PKC apicalpolarity complex leading to enhanced nuclear localization of Yap while models that restore salivaryfunction have repaired apical polarity and reduced nuclear localization of Yap. We propose to developa model that integrates each phase of wound healing detailing the interactions between phases andthe impact of nuclear Yap on the progression through these phases. The outcomes from this workinclude: 1) inputs regulating sustained Yap nuclear translocation 2) ability of chronic nuclear Yap toprevent re-differentiation after IR 3) when/if Yap is necessary for restoration of salivary gland function4) uncovering the interplay between wound healing phases that prevent restoration of salivary glandfunction. Understanding this process would have a positive impact by revealing intervention points thatpromote restoration of salivary gland function.