THE ROLE OF NEUTROPHILS IN INFLAMMATION AND VASCULAR REMODELING IN PSORIASIS - PROJECT SUMMARY PSORIASIS IS A COMMON AND CHRONIC CONDITION EFFECTING OVER 7 MILLION ADULTS IN THE UNITED STATES WITH A SIGNIFICANT COST TO THE HEALTHCARE SYSTEM AND BURDEN ON INDIVIDUAL QUALITY OF LIFE. NO CURE EXISTS AND WHEN TARGETED TREATMENT OPTIONS FAIL, PATIENTS MAY REQUIRE SYSTEMIC MEDICATIONS INCLUDING IMMUNOSUPPRESSANTS WITH SIGNIFICANT SIDE EFFECTS. THERE REMAINS A SIGNIFICANT NEED FOR ADDITIONAL SAFE AND EFFECTIVE TREATMENT OPTIONS. WHILE PSORIASIS IS LARGELY A T-CELL DEPENDENT DISEASE, CERTAIN OF ITS FEATURES AS WELL AS SOME CLINICAL OBSERVATIONS INDICATE A POSSIBLE ROLE FOR NEUTROPHILS (PMN) IN ITS PATHOGENESIS. THIS ROLE, HOWEVER, REMAINS POORLY UNDERSTOOD; SOME PRIOR STUDIES HAVE INDICATED PMN MAY CONTRIBUTE TO WORSENING DISEASE WHILE OTHERS HAVE INDICATED PMN MAY PLAY AN ANTI-INFLAMMATORY ROLE. PMN ARE THE MOST ABUNDANT LEUKOCYTE IN HUMANS AND ARE THE IMMUNE SYSTEM'S FIRST RESPONDERS. THEY HAVE BEEN SHOWN TO INTERACT WITH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS THROUGH THEIR RECRUITMENT OF OTHER LEUKOCYTES BY RELEASE OF PRO-INFLAMMATORY CHEMOKINES AND CYTOKINES, SETTING OFF AN INFLAMMATORY CASCADE. THEY ALSO HAVE THE ABILITY TO INFLUENCE VASCULAR REMODELING, A KEY HISTOPATHOLOGICAL FEATURE OF PSORIASIS, THROUGH THEIR RELEASE OF PRO-ANGIOGENIC CYTOKINES. MANY PSORIASIS THERAPIES IMPACT PMN BUT IT REMAINS UNCLEAR TO WHAT EXTENT THIS INFLUENCES OUTCOMES. BETTER UNDERSTANDING THE ROLE OF PMN IN PSORIASIS IS OF VITAL IMPORTANCE, AS IT MAY HELP TO REFINE FUTURE TREATMENT EFFORTS. BASED ON OUR PRELIMINARY DATA AND PRIOR LITERATURE ON THE TOPIC, OUR CENTRAL HYPOTHESIS IS THAT PMN MIGRATE TO LESIONAL AREAS EARLY IN DISEASE AND ACT AS A CATALYST FOR ANGIOGENESIS AND THE RECRUITMENT OF OTHER IMMUNE CELLS. THEREFORE, DEPLETING PMNS WILL REDUCE VASCULAR CHANGES, THE RECRUITMENT OF OTHER LEUKOCYTE TYPES, AND THUS VISIBLE SIGNS OF INFLAMMATION. WE WILL TEST THIS HYPOTHESIS THROUGH THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE THE ROLE OF PMN ON THE INFLAMMATORY MILIEU IN PSORIATIC INFLAMMATION, AND 2) DETERMINE THE ROLE OF PMN ON VASCULAR REMODELING IN PSORIATIC INFLAMMATION. SUCCESSFUL COMPLETION OF THESE AIMS WILL ALLOW US TO PURSUE A MORE THERAPEUTICALLY RELEVANT APPROACH TO BLOCK LEUKOCYTE INFLUX AT A STAGE IN THE DISEASE WHEN PMNS ARE PARTICULARLY RELEVANT TO DISEASE EXACERBATION. OUR LAB IS WELL POSITIONED TO PERFORM THIS RESEARCH BECAUSE OF SEVERAL IMPORTANT RESOURCES AVAILABLE TO US. FIRSTLY, OUR LAB AND INSTITUTION HAVE SIGNIFICANT EXPERIENCE IN PMN RESEARCH, INCLUDING A NEWLY ESTABLISHED NEUTROPHIL CONSORTIUM AIMED AT STUDYING PMNS IN LUNG INJURY. SECONDLY, NORTHWESTERN'S SKIN BIOLOGY AND DISEASES RESOURCE-BASED CENTER HAS SEVERAL CORE FACILITIES AND RESEARCHERS WELL PRACTICED IN THE DISEASE AND MODELS WE PROPOSE TO USE WHO CAN GIVE ADVICE AND EXPERTISE. LASTLY, OUR LAB AND CORES HAVE THE ANIMALS, FACILITIES, AND REAGENTS NECESSARY TO DO THIS WORK, INCLUDING GENETICALLY MODIFIED MICE WITH FLUORESCENT PMNS, A MULTIPHOTON MICROSCOPE FOR INTRAVITAL IMAGING, ROBUST METHODS TO DEPLETE PMNS AND VALIDATE DEPLETION, AND METHODS TO GENERATE 3D RAFT CULTURES OF HUMAN SKIN FOR IN VITRO ASSAYS.