PROJECT SUMMARY/ABSTRACT Despite the clinical and psychosocial burden of itch in atopic dermatitis (AD), effective treatment options are limited. Interleukin-31 (IL-31), an inflammatory factor produced by skin T cells, has emerged as a powerful mediator of both itch and rash. When administered to skin, IL-31 can trigger dermatitis and activate cutaneous afferent sensory nerves to drive scratching behavior. Therapeutic antibodies directed against IL-31 and its receptor, IL31RA, have shown promise in clinical trials for AD and chronic pruritus. Yet fundamental questions about IL-31 biology remain. Which cells make IL-31? What pathways does IL-31 actuate in sensory afferent neurons? How do IL-31 signals integrate with other pruritogenic pathways in the context of inflammation? Improved definitions of the sources, pathways, and effector functions of IL-31 will substantially advance mechanistic understanding of the links between inflammation and itch. Dr. Fassett’s long-term research goal is to elucidate cellular and molecular mechanisms responsible for atopy-associated pruritus. The objective of this proposal is to use genetic mouse models to address the in vivo biology of IL-31 by examining the effects of endogenous IL-31 on cutaneous inflammation and pruritus sensory pathways. Dr. Fassett’s central hypothesis is that IL-31 couples itch and rash via its combined effects on pruritoceptive afferent pathways and cutaneous Th2 cytokine-mediated inflammation. Dr. Fassett will test this hypothesis using three specific aims. In Aim 1, Dr. Fassett will use novel IL31-deficient animals and IL31- tdTomato reporter animals to determine how multiple IL-31 source cell types functionally impact cutaneous Th2 inflammation in vivo. In Aim 2, she will elucidate the contribution of IL-31:IL31RA to atopy-associated pruritoceptive pathways including itch sensation and neurogenic inflammation. In Aim 3, she will determine how IL-31 alters afferent responses to other pruritogens, including Th2 cytokines. This project is relevant to the mission of NIAMS because it explores the mechanism of action of IL-31, a biologic target of potentially great therapeutic value for atopic dermatitis and for pruritus associated with other inflammatory skin diseases. Dr. Fassett is an MD PhD-trained Dermatologist working as a post-doctoral research fellow at the University of California, San Francisco. She is applying for a K08 Award to support her goal of becoming an independent physician scientist. UCSF’s exceptional training environment will support her efforts. Critical elements of her career development plan include mentorship by Dr. Mark Ansel, expert in cytokine biology and Th2 inflammation;; co-mentorship by Dr. Allan Basbaum, expert in pain and itch;; guidance by a mu...