PROJECT SUMMARY Taste nerves, like other peripheral nerves, have the potential to regenerate after injury but patients are often left with lasting sensory deficits. Better understanding of mechanisms that regenerate sensory target cells is needed to address this problem. Taste buds degenerate when their associated nerve is damaged, but are reformed and become functional through largely unknown mechanisms. In preliminary studies, mice lacking the interleukin-1 receptor (IL-1R) gene show profound delays in taste bud regeneration, reinnervation, and the recovery of neural taste responses. The IL-1R is activated by the master immune regulatory cytokines, IL- 1? and IL-1?, or IL-1?. After damage to other peripheral nerves, IL-1 recruits immune cells known as ?leukocytes? which promote the regrowth of peripheral axons. Taste buds express IL- 1 family members (including the IL-1R), as do leukocytes attracted to the tongue by taste bud denervation. In the proposed studies, we test the hypothesis that IL-1R signaling in taste buds and leukocytes promotes the recovery of taste function after injury. We will test this hypothesis using full IL-1R knockout mice, mice treated with a form of the endogenous IL-1R inhibitor, and mice with IL-1R deletion in leukocytes or in taste buds. Our aims are to: (1) Determine the role of IL-1R signaling in taste bud regeneration and the recovery of taste function after injury, and the temporal requirements for its signaling; and (2) Determine whether IL-1R signaling in leukocytes and/or taste receptor cells is required for taste bud degeneration, regeneration, and functional recovery after nerve injury. We propose that IL-1R regulates immune responses to taste bud degeneration, and promotes the proliferation and differentiation of taste progenitors later during taste bud regeneration. These results will provide insight to fundamental mechanisms that rebuild taste buds in adulthood, and a novel, possibly clinically-useful signaling pathway used in the recovery of sensory function after injury.
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