ABSTRACT According to the American Cancer Society, more than 60,000 people will develop head and neck cancer this year and those patients must receive radiation therapy to survive. This treatment regularly destroys the salivary glands (SG), leading to a loss of secretory function which is typically permanent. Current treatments remain largely ineffective, with therapeutic interventions being limited to use of saliva substitutes with modest effectiveness and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore SG functioning is essential. In response to the challenges noted above, we propose introduction of FGF7 and FGF10, both of which activate FGF2b signaling to promote SG epithelial morphogenesis and differentiation (Aims 1 and 2, in vitro and in vivo, respectively). Having fortified our scaffold to enhance SG morphogenesis and differentiation, we will nonetheless still be faced with absent or poorly developed vasculature and nerve systems, as indicated by repeated studies demonstrating loss of vascularization and innervation in irradiated SG. In response to these challenges, we will draw on our previous findings indicating VEGF and FGF9 to aid vascular formation and neurotrophic factors (e.g., NGF) to promote innervation (Aim 3). We hypothesize that a modified FH scaffold containing immobilized L1 peptides (L1p) and GF (L1p-GF-FH) will promote formation of functional tissue in irradiated SG. Aim 1: will demonstrate sustained secretory function using a fortified scaffold in vitro. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in irradiated SG. Aim 2: will demonstrate sustained secretory function using a fortified scaffold in vivo. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in an irradiated SMG mouse model. Aim 3: will restore full functionality to irradiated SG in vivo. We will combine our Ep-FH scaffold with polymeric microparticles to release pro-angiogenic and pro-innervation GF in a temporal sequence, mimicking the in vivo physiology, to enhance functional recovery of SMG following radiation treatment. In summary, our proposed studies will extend our findings to date using L1p to restore SG function, thereby allowing for both greater sustainability and a deeper degree of functionality.