PROJECT SUMMARY The sense of taste is important for nutrition and quality of life. Taste buds on the anterior tongue connect to the chorda tympani (CT) nerve, which transmits taste information to the brain. CT axons maintain adult taste bud structure and function, but trauma, infection, and ear surgery can damage taste nerves leading to taste bud degeneration and taste deficits. The CT and associated taste buds regenerate after experimental nerve sectioning and restore taste function in normal mice, but taste dysfunction often persists in humans. In contrast to taste development, we have a poor understanding of injury-induced mechanisms responsible for rebuilding taste buds in adults. Our overall goal is to identify neuroimmune mechanisms mediating taste bud regeneration to provide strategies to restore taste function after injury and disease. Cytokine receptor signaling has diverse inflammatory and pro-regenerative effects in injured complex tissues. We previously demonstrated that interleukin (IL)-1 signaling through its receptor is critical for taste bud regeneration and the recovery of neural taste responses. Our preliminary results indicate that signaling through the tumor necrosis factor receptor (TNFR1) is also needed for taste bud regeneration, likely through different mechanisms than IL-1R. We hypothesize that TNFR1 and IL1R signaling activate downstream nuclear factor (NF)-κB, potentially in different cell types, to stimulate the proliferation and differentiation of new taste receptor cells. We propose a comprehensive neuroimmune approach in injured mice deficient in system-wide Tnfr1 and taste cell-specific or immune cell-specific Il1r, Tnfr1, and Rela (a major subunit of NFκB). Our aims are to: (1) Determine the requirement for TNFR1 signaling in taste bud regeneration and the recovery of neural taste function after CT axotomy; (2) Dissect the cellular requirements for TNFR1 and IL-1R signaling in the injured peripheral taste system; and (3) Identify converging intracellular signaling mechanisms through (NF)-κB that promote taste bud regeneration. Together these studies will illuminate complex, injury-mediated mechanisms that promote adult taste bud regeneration and restore the sense of taste.