Project Grant R21OD034470

A VALIDATED MOUSE MODEL OF BROWN FAT TARGETING - ABSTRACT/PROJECT SUMMARY MICE AND HUMAN PHYSIOLOGY ARE DEEPLY AFFECTED BY BROWN FAT THROUGH ITS CONTROL OF METABOLIC HOMEOSTASIS AND PRODUCTION OF SIGNALING MOLECULES. AS SUCH, BROWN FAT SPECIFIC GENETIC MODIFICATIONS IN MICE HAVE ARISEN AS A TRULY RELEVANT TOOL TO UNDERSTAND BROWN FAT ROLE IN CONTROLLING PHYSIOLOGY WITH APPLICATIONS IN AN ARRAY OF ORGAN SYSTEMS. FOR THIS, CRE-RECOMBINASE DRIVERS UNDER CONTROL OF THE UCP1 PROMOTER HAVE BEEN USED. IN THIS PROPOSAL, WE SHOW THAT THE MOST COMMONLY USED MOUSE MODEL OF BROWN FAT TARGETING IS THE SOURCE OF SOME PREVIOUSLY UNNOTICED NEGATIVE EFFECTS. THUS, OUR PRELIMINARY DATA SUPPORTS AN UNMET CRITICAL NEED TO GENERATE A NEW MOUSE MODEL TO TARGET MATURE BROWN ADIPOCYTES IN AN EFFICIENT AND SAFE MANNER. FOR THESE REASONS, THE MAIN GOALS OF THIS APPLICATION ARE TO GENERATE (AIM 1), VALIDATE (AIM 2) AND MAKE WIDELY AVAILABLE (AIM 3) A NEW MODEL OF BROWN FAT TARGETING. FOR THIS, WE WILL USE AN INNOVATIVE BUT VALIDATED CRISPR/CAS9 TARGETING TECHNIQUE TO INSERT CRE-RECOMBINASE DRIVEN BY A DEFINED UCP1 PROMOTER INTO A SAFE HARBOR LOCATION. NEXT, WE WILL USE CRE-MEDIATED LINEAGE TRACING TECHNIQUES TO ADDRESS ITS CELLULAR SPECIFICITY. DUE TO THE BROAD INTEREST IN BROWN FAT BIOLOGY, THIS MOUSE MODEL IS ANTICIPATED TO BE BROADLY USED BY SCIENTISTS IN AN ARRAY OF FIELDS OF INTEREST TO MULTIPLE NIH INSTITUTES. THIS NEW MOUSE MODEL OF BROWN FAT TARGETING IS EXPECTED TO HAVE A POSITIVE IMPACT AS A STEP FORWARD TOWARDS DEVELOPING BETTER PRECLINICAL MOUSE MODELS. WE WILL MAKE OUR NEW MODEL AVAILABLE TO THE COMMUNITY THROUGH A MOUSE REPOSITORY. FOR THESE REASONS, THIS PROPOSAL IS DIRECTED TO THE FOA PAR-21-167, "DEVELOPMENT OF ANIMAL MODELS AND RELATED MATERIALS FOR RESEARCH".