Abstract:More than 73% of head and neck cancer patients continue to suffer from the chronic consequences of xerostomiamonths to years after the completion of radiotherapy making this one of the most compelling issues in salivarygland biology. Despite technological advancements in cancer therapies collateral damage to salivary glandsremains 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 themolecular stages of damage. The overall vision (long-term goal) is to restore salivary gland function in patientsfollowing radiotherapy by identifying healing stages in salivary glands that lead to the stratification andadministration of precise therapeutics for their stage. This proposal will integrate metabolic changes at three timepoints of radiation-induced dysfunction that build a mechanistic foundation to bridge to clinical therapeuticinterventions. We hypothesize that changes in salivary gland metabolism enable the loss of function phenotypefollowing radiation treatment of salivary glands. The outcomes from this work include: 1) Metabolic networksthat are kinetically altered following IR 2) Identification of novel regulators of the metabolic phenotype followingIR 3) Linkage of changes in metabolic networks with cellular mechanisms that are involved in the response ofsalivary glands to IR damage. Understanding this process would have a positive impact by revealing interventionpoints that promote restoration of salivary gland function.