Project Grant F30ES038428

THE ROLE OF THE ARYL HYDROCARBON RECEPTOR AND MICROBIOME IN THE SKIN DISEASE HIDRADENITIS SUPPURATIVA - PROJECT SUMMARY HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY NODULES, ABSCESSES, AND SCARRING IN INTERTRIGINOUS AREAS SUCH AS THE AXILLAE AND GROIN, AND IT IS HIGHLY ASSOCIATED WITH OBESITY, SMOKING, POVERTY, AND THE FEMALE SEX. THE ONLY FDA-APPROVED THERAPIES HAVE LOW RESPONSE RATES BECAUSE THEY WERE ORIGINALLY DESIGNED TO TREAT PSORIASIS. A SIGNIFICANT OBSTACLE TO DEVELOPING BETTER MEDICATIONS IS OUR LIMITED UNDERSTANDING OF HS, AND A HURDLE TO BUILDING THIS KNOWLEDGE IS THE LACK OF AN APPROPRIATE IN VIVO MODEL. PREVIOUS WORK IN THE GARZA LAB HAS ESTABLISHED THAT PLASTIC-ASSOCIATED ENDOCRINE DISRUPTORS (PEDS) FOUND IN ULTRA-PROCESSED FOODS (UPFS) AND HS TISSUE RECAPITULATE CORE FEATURES OF HS IN VITRO; NAMELY, FIBROBLASTS TREATED WITH BISPHENOLS AND PHTHALATES DOWNREGULATE EXPRESSION OF THE PROTEIN NICASTRIN (NCSTN), WHICH IS MUTATED IN INBORN, MONOGENIC HS. HOWEVER, THE PATHWAY THROUGH WHICH PEDS ELICIT THESE EFFECTS IS STILL UNCLEAR, BUT THE PARALLELS BETWEEN HS AND CHLORACNE PROVIDE INSIGHT. CHLORACNE IS AN ACNEIFORM DERMATOSIS WITH STRIKING SIMILARITIES TO HS IN BOTH SKIN PHENOTYPE AND ASSOCIATED COMORBIDITIES. CHLORACNE IS OFTEN CAUSED BY POLYCHLORINATED BIPHENYLS (PCBS) ACTIVATING THE ARYL HYDROCARBON RECEPTOR (AHR). EVIDENTLY, PCBS CAUSING CHLORACNE PARALLELS PEDS PROMOTING HS, WHICH MOST LIKELY ALSO INVOLVES AHR. ADDITIONALLY, HS IS CHARACTERIZED BY AN ALTERED SKIN MICROBIOME THAT MAY BE FURTHER PROMOTING AHR ACTIVATION, ENHANCED BY PCB PERTURBATION. IN THIS PROPOSAL, I WILL CONDUCT A SERIES OF CELL-BASED EXPERIMENTS TO FURTHER DEFINE THE ETIOLOGY OF HS TO LAY A FOUNDATION FOR THE DEVELOPMENT OF IMPROVED DRUGS TO TREAT THIS DISEASE. TO DEVELOP A KNOWLEDGE BASE FOR DEVELOPING THERAPIES FOR HS, I WILL (SPECIFIC AIM 1) INVESTIGATE THE MOLECULAR PATHWAYS BY WHICH PEDS CONTRIBUTE TO HS. TO ACCOMPLISH THIS, I WILL ANALYZE HOW PED TREATMENT OF FIBROBLASTS AND KERATINOCYTES RECAPITULATES HS THROUGH PROTEOMICS SEQUENCING. BECAUSE OF THE PARALLELS OF HS:CHLORACNE AND PEDS:PCBS, I PREDICT THAT THESE ANALYSES WILL ELUCIDATE THE ROLE OF AHR, WHOSE FUNCTIONALITY I WILL THEN TEST IN VITRO. BECAUSE DYSREGULATED METABOLISM CHARACTERIZES THE HOST-MICROBE INTERFACE IN HS, I WILL NEXT (SPECIFIC AIM 2) CHARACTERIZE HOW MICROBIAL DYSBIOSIS ALTERS AHR SIGNALING IN HS PATHOGENESIS. I WILL ASSESS HOW CORYNEBACTERIUM, A GENUS PARTICULARLY ENRICHED IN THE HS SKIN MICROBIOME, PRODUCES TRYPTOPHAN PRECURSORS AND METABOLITES THAT I EXPECT TO ACTIVATE AHR AND REDUCE NCSTN IN SKIN CELLS, RECAPITULATING HS. I PREDICT THAT PERTURBING CORYNEBACTERIUM WITH PEDS WILL FURTHER EXACERBATE THIS PHENOTYPE. THROUGH THESE STUDIES, I WILL INCREASE OUR UNDERSTANDING OF HOW ENVIRONMENTAL EXPOSURES ALTER MOLECULAR PATHWAYS TO DRIVE HS. THESE FINDINGS WILL BE INSTRUMENTAL IN DEVELOPING CURRENTLY-LACKING THERAPIES FOR HS; FOR EXAMPLE, AN INTRIGUING OUTCOME OF THIS PROJECT WOULD BE IF COMPONENTS OF THE HEALTHY SKIN MICROBIOME COULD BE USED THERAPEUTICALLY TO TREAT THIS CONDITION.