INVESTIGATING NEURO-IMMUNE INTERACTIONS IN PULMONARY HOMEOSTASIS AND DISEASE - PROJECT SUMMARY THE LUNG IS A CRITICAL BARRIER TISSUE, CONTINUALLY EXPOSED TO THE EXTERNAL ENVIRONMENT AND RESPIRATORY INSULTS. INFLAMMATION IS THE APPROPRIATE RESPONSE TO RESPIRATORY INSULTS; HOWEVER SUSTAINED OR PROLONGED INFLAMMATION CAN EXACERBATE THE INJURY ITSELF. ONE, LARGELY FATAL, OUTCOME OF SUSTAINED INFLAMMATION IS INTERSTITIAL LUNG DISEASE (ILD)-A GROUP OF PATHOLOGIES CHARACTERIZED BY INFLAMMATION, LUNG DAMAGE, AND OFTEN FIBROSIS. THE CAUSATIVE FACTORS OF ILD ARE TYPICALLY UNKNOWN, OR IDIOPATHIC, THOUGH THERE IS A GROWING BODY OF EVIDENCE DETAILING ILD ETIOLOGY LINKED TO SELECT PHARMACEUTICAL EXPOSURE. CLINICAL REPORTS SHOW THAT MODULATION OF NEUROPEPTIDE CALCITONIN GENE RELATED PEPTIDE (CGRP), OR DISRUPTION OF IMMUNE TOLERANCE CAN PROMOTE ILD. DENDRITIC CELLS (DCS) REPRESENT THE BRIDGE BETWEEN THESE OBSERVATIONS, AS MY PRELIMINARY DATA SHOW THAT HUMAN AND MURINE DCS EXPRESS THE CGRP RECEPTOR AND CLOSELY ASSOCIATE WITH CGRP+ SENSORY AXONS (NOCICEPTORS) SURROUNDING THE AIRWAY. DCS ARE KNOWN TO ACCUMULATE IN FIBROTIC ILD, A PATHOLOGY CONSERVED IN PRECLINICAL MODELS. I OBSERVED THAT PULMONARY NOCICEPTORS DISPLAY EXTENSIVE NEUROPLASTICITY IN A PRE-CLINICAL MODEL OF ILD, WHERE THEY BRANCH TOWARD DC-ENRICHED FIBROTIC LESIONS AND RELEASE CGRP. DCS ACT AT THE INTERFACE OF IMMUNITY WHERE THEY HAVE TWO MAJOR DIVISIONS: (I) IMMUNOGENIC DCS PROMOTE THE IMMUNE RESPONSE THROUGH T-CELL ACTIVATION AND (II) TOLEROGENIC DCS INITIATE PERIPHERAL TOLERANCE THROUGH REGULATORY T-CELLS. INTRIGUINGLY, FOLLOWING NOCICPETOR BRANCHING AND CGRP RELEASE, CLUSTERS OF PD-L1+ TOLEROGENIC DCS AND REGULATORY T-CELLS ARE OBSERVED. INTEGRATION OF THESE DATA WITH TRANSCRIPTIONAL ANALYSES SUPPORTS THE HYPOTHESIS THAT NEURO-IMMUNE INTERACTIONS ACTIVATE AND REWIRE DCS TOWARD THE TOLEROGENIC FATE VIA CGRP SIGNALING. USING PHARMACOLOGIC APPROACHES TO MODULATE CGRP SIGNALING, THIS PROPOSAL WILL INVESTIGATE THE STRUCTURE OF NOCICEPTOR-DC INTERACTIONS AND DEFINE THE TRANSCRIPTIONAL AND FUNCTIONAL IMPACT OF CGRP SIGNALING ON PULMONARY DC BIOLOGY. WITH SUPPORT FROM MY SPONSORS, COMMITTEES, AND COLLABORATORS-THIS PROJECT WILL PROVIDE TRAINING IN PULMONARY NEUROIMMUNOLOGY AS WELL AS NEW TECHNICAL AND ANALYTIC SKILLS. TECHNOLOGY AND EXPERTISE TO SUPPORT THIS TRAINING ARE IN PLACE. THIS RESEARCH IS ALSO SUPPORTED BY THE LITERATURE WHERE ANTI-INFLAMMATORY EFFECTS OF CGRP SIGNALING HAVE BEEN DEMONSTRATED. FURTHER UNDERSTANDING THE SIGNALS THAT REGULATE TOLEROGENIC DCS ARE OF SIGNIFICANT CLINICAL INTEREST; TOLEROGENIC DC THERAPY CAN BE USED TO MANAGE AUTOIMMUNE DISEASE AND OTHER INFLAMMATORY CONDITIONS, AND MAY ALSO REPRESENT A UNIQUE CLINICAL STRATEGY FOR THE MANAGEMENT OF ILD.