Project Grant R03AI185412

METABOLOMICS AND TRANSCRIPTOMICS ANALYSES OF CELL-SPECIFIC REGULATION OF FATTY ACID SYNTHESIS AND METABOLIC REPROGRAMMING IN SKIN INFLAMMATION - ABSTRACT CELL METABOLISM PLAYS A CRUCIAL ROLE IN REGULATING THE ACTIVATION OF IMMUNE CELLS IN HOST DEFENSE TO INFECTION AND THE DEVELOPMENT OF INFLAMMATORY DISEASES. DIFFERENT ASPECTS OF CELL METABOLISM CAN REGULATE THE ACTIVATION OF IMMUNE CELLS TOWARD PRO-INFLAMMATORY OR ANTI-INFLAMMATORY RESPONSES. THUS, PROPER METABOLIC REPROGRAMMING IN IMMUNE CELLS IS CRUCIAL TO MAINTAINING ACTIVE IMMUNITY, WHILE ABERRANT REGULATION OF IMMUNE CELL METABOLISM CAN CONTRIBUTE TO DISEASE DEVELOPMENT. EMERGING EVIDENCE INDICATES THAT FATTY ACID SYNTHESIS PLAYS A CRUCIAL ROLE IN IMMUNITY AND DISEASE DEVELOPMENT SINCE FATTY ACIDS ARE KEY COMPONENTS OF CELLULAR PROCESSES INCLUDING MEMBRANE FUNCTION, SIGNAL TRANSDUCTION, AND ENERGY GENERATION. RECENT STUDIES SUGGEST THAT FATTY ACID SYNTHESIS IS CLOSELY ASSOCIATED WITH A PRO-INFLAMMATORY PHENOTYPE OF IMMUNE CELLS AND THE DEVELOPMENT OF SOME INFLAMMATORY DISEASES, IMPLYING THAT MODIFICATIONS IN FATTY ACID SYNTHESIS CAN BE USED AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF METABOLIC AND INFLAMMATORY DISEASES. WE FOUND THAT INHIBITION OF FATTY ACID SYNTHASE (FASN), THE CENTRAL ENZYME OF FATTY ACID SYNTHESIS, SIGNIFICANTLY ALLEVIATED THE PATHOLOGY OF IMIQUIMOD (IMQ)-INDUCED PSORIASIS-LIKE SKIN INFLAMMATION IN MICE BY REDUCING THE INFLAMMATORY RESPONSES IN IMMUNE CELLS AND SKIN. HOWEVER, THE DETAILED MECHANISM OF FATTY ACID SYNTHESIS-DEPENDENT SKIN INFLAMMATION IS NOT CLEAR DUE TO THE SYSTEMIC AND NON-CELL TYPE-SPECIFIC EFFECTS OF THE INHIBITORS. ADDITIONALLY, IT IS NOT CLEAR HOW CELL METABOLISM IN IMMUNE CELLS OR SKIN TISSUES CHANGES DURING THE DEVELOPMENT OF SKIN INFLAMMATION AND HOW THE INHIBITION OF FATTY ACID SYNTHESIS AFFECTS METABOLIC REPROGRAMING. TO UNDERSTAND THE ROLE OF FATTY ACID SYNTHESIS IN CELLS AND TISSUES IN SKIN INFLAMMATION, WE WILL GENERATE CELL- SPECIFIC FASN-DEFICIENT MICE AND EXAMINE HOW INHIBITION OF FATTY ACID SYNTHESIS AFFECTS THE OTHER METABOLIC PATHWAYS IN IMMUNE CELLS AND SKIN TISSUES. WE WILL BE ABLE TO BETTER UNDERSTAND THE PREVIOUSLY UNIDENTIFIED ROLE AND REGULATORY MECHANISM OF FATTY ACID SYNTHESIS IN IMMUNE CELLS AND PSORIASIS. THE PROPOSED STUDIES WILL HELP US BETTER UNDERSTAND THE METABOLIC REGULATION OF IMMUNE CELLS AND WILL LEAD TO NOVEL INSIGHTS INTO FATTY ACID SYNTHESIS AND IMMUNE FUNCTION IN THE CONTEXT OF SKIN DISEASE. BY IDENTIFYING PREVIOUSLY UNCHARACTERIZED DISTINCT AND SPECIFIC PATHWAYS REGULATED BY FATTY ACID SYNTHESIS, WE WILL BE ABLE TO EXPAND OUR KNOWLEDGE TO OTHER INFLAMMATORY DISEASES SUCH AS ARTHRITIS AND INFLAMMATORY BOWEL DISEASES, WHICH WILL FURTHER GUIDE US IN DEVELOPING NOVEL TARGETED THERAPIES FOR TREATING AUTOIMMUNE DISEASES, METABOLIC DISORDERS, AND INFLAMMATORY DISORDERS.