Ineffective wound healing responses enable chronic radiation-induced salivary gland dysfunction

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Abstract: More than 73% of head and neck cancer patients continue to suffer from the chronic consequences of xerostomia months to years after the completion of radiotherapy making this one of the most compelling issues in salivary gland biology. Despite technological advancements in cancer therapies, collateral damage to salivary glands remains a significant problem for these patients and severely diminishes their quality of life. The field of radiation-induced salivary gland damage is severely hampered by the lack of a comprehensive model detailing the molecular stages of damage. The overall vision is to restore salivary gland function in patients following radiotherapy by identifying healing stages in salivary glands that lead to the stratification and administration of precise therapeutics for their stage. This proposal will use the sequential phases of wound healing involving inflammation to its resolution and reconstitution of tissue through proliferation and differentiation of epithelial tissue as steps to accomplish this vision. We hypothesize that irradiated salivary glands fail to efficiently progress through the wound healing phases leading to prolonged dysfunction. Our prior work has demonstrated that radiation-induced proliferation in salivary glands is due in part to disruption of the PKCζ apical polarity complex leading to enhanced nuclear localization of Yap, while models that restore salivary function have repaired apical polarity and reduced nuclear localization of Yap. We propose to develop a model that integrates each phase of wound healing detailing the interactions between phases and the impact of nuclear Yap on the progression through these phases. The outcomes from this work include: 1) inputs regulating sustained Yap nuclear translocation, 2) ability of chronic nuclear Yap to prevent re-differentiation after IR, 3) when/if Yap is necessary for restoration of salivary gland function, 4) uncovering the interplay between wound healing phases that prevent restoration of salivary gland function. Understanding this process would have a positive impact by revealing intervention points that promote restoration of salivary gland function.