Project Summary/Abstract Research: Peripheral neuropathy, a condition involving damage to the peripheral nervous system (PNS), affects more than 20 million people in the United States. Protection and restoration of PNS is of particular relevance upon barrier tissue injury, a leading cause of PNS damage, to promote somatosensory recovery and regulate pain. Of note, injury and repair at the barrier tissues occur in the context of commensal microbiota-specific T cell responses. Indeed, reactive commensal-specific T cells promote wound healing and sensory neuron regeneration upon injury. However, how commensal-specific T cells contribute to PNS restoration upon injury, and what the long-term consequences of the T cell response are on pain sensation, represent a fundamental yet unexplored area of research. My preliminary data show that Interleukin 17A (IL-17A) produced by commensal-specific T cells signals to sensory neurons via the IL-17 receptor A (IL-17RA), the transcription of which is upregulated in injured neurons, promoting sensory nerve regeneration. However, neither the upstream factors controlling IL-17RA upregulation nor the downstream signaling and transcriptomic regulation has been formally studied in injured neurons. My overarching hypothesis is that commensal-specific T cells control PNS regeneration in the skin upon injury and regulate long-term pain sensation via IL-17A/IL-17RA signaling. To assess my hypothesis and the potential neurotrophic function of IL-17A, I will study how IL-17A enhances PNS regeneration (Aim 1 and 2), and the long-term consequences on pain sensation (Aim 3) in three complementary mouse models of nerve injury: (i) ear skin punch, for mechanistic insights into nerve regeneration; (ii) sciatic nerve transection (SNT), for therapeutic evaluation of IL-17A; and (iii) footpad skin injury, which allows the use of standard tests to asses pain sensation. Career goals: My long-term goal is to become an independent investigator at an academic institution, where I will explore the communication between the immune and peripheral nervous systems at barrier sites in response to the microbiota, ultimately translating my findings into novel therapies to treat neuroimmune-related disabilities. I also aspire to become an inspirational mentor and teacher. Career development: I will meet weekly with Dr. Belkaid and discuss my progress with collaborators every 6 months for the duration of the award. Before the K award, I will improve my bioinformatics skills (advance bioinformatics courses), attend at least to 2 international conferences (oral presentation), attend NIH training courses (teaching and mentoring workshops and laboratory management). Environment: The NIH Intramural Research Program has more than 1,200 PIs conducting basic, translational, and clinical research. It is a unique environment with resources for the career development (including microbiome, pain study center and immunology core facilities, and frequent semina...