Project Grant R21HD112649

DEVELOPING A BABOON MODEL FOR UTERINE FIBROIDS - BY AGE 50, MOST WOMEN WILL HAVE HAD UTERINE LEIOMYOMAS (FIBROIDS) WITH A LIFETIME CUMULATIVE INCIDENCE OF ~70% FOR WHITE WOMEN AND >80% FOR BLACK WOMEN. APPROXIMATELY 25% OF WOMEN WITH FIBROIDS EXPERIENCE SYMPTOMS SEVERE ENOUGH TO CAUSE THEM TO SEEK CLINICAL CARE. ALTHOUGH THEY ARE A SIGNIFICANT HEALTHCARE BURDEN FOR MANY INDIVIDUALS, THE ETIOLOGY AND PATHOPHYSIOLOGY OF FIBROIDS IS POORLY UNDERSTOOD. FIBROIDS ARE THE MOST COMMON REASON FOR HYSTERECTOMY IN THE US, YET FIBROID INCIDENCE AND SYMPTOMATOLOGY ARE POORLY UNDERSTOOD. THE CURRENT GAP IN KNOWLEDGE ABOUT THE ETIOLOGY AND PATHOPHYSIOLOGY OF THE DISEASE HAS CONTRIBUTED TO THE LACK OF SAFE AND EFFECTIVE LONG-TERM STRATEGIES FOR WOMEN WITH THE DISEASE. VERY LITTLE IS KNOWN ABOUT THE UNDERLYING MECHANISMS THAT LEAD TO FIBROID DEVELOPMENT. ONE OF THE MAIN REASONS THAT FIBROID BIOLOGY IS POORLY UNDERSTOOD IS THE LACK OF A GOOD MODEL SYSTEM TO STUDY THE DISEASE. PERHAPS, THE BEST MODEL AVAILABLE IS A KIDNEY CAPSULE XENOGRAFT MODEL IN IMMUNOCOMPROMISED MICE BUT THEIR TRANSLATIONAL POTENTIAL IS NOT CLEAR. SEVERAL OTHER ANIMAL MODELS, INCLUDING SOME GENETICALLY MODIFIED MICE, HAVE BEEN PROPOSED FOR FIBROID RESEARCH, BUT EACH HAS SIGNIFICANT LIMITATIONS THAT PREVENT THEIR WIDESPREAD USE IN THE LABORATORY. OUR GOAL IS TO DEVELOP A STANDARDIZED AND RELIABLE ORTHOTOPIC BABOON MODEL FOR UTERINE FIBROID RESEARCH, WHICH WE PROPOSE TO DO IN TWO PHASES. THERE ARE SEVERAL REASONS FOR CHOOSING THE BABOON FOR THIS PURPOSE. THE BABOON IS NOT ENDANGERED, HAS BEEN USED BY MANY LABORATORIES TO STUDY REPRODUCTIVE BIOLOGY BECAUSE OF THE SPECIES PHYLOGENETIC SIMILARITY TO HUMANS AND MOST IMPORTANTLY, BABOONS DEVELOP SPONTANEOUS UTERINE FIBROIDS, THEMSELVES, A TRAIT SHARED BY ALL PRIMATES EXAMINED. IN PHASE 1 OF THE PROJECT, WE PROPOSE TO DEVELOP STABLE, IMMORTALIZED, AND CLONAL BABOON MYOMETRIAL CELL LINES THAT MIMIC UTERINE FIBROID CELLS FROM HUMAN AS CLOSELY AS POSSIBLE WITH THE FOLLOWING AIMS: ESTABLISH BABOON IMMORTALIZED MYOMETRIAL CELL LINES THAT CORRESPOND TO THE MOST COMMON GENETIC SUBTYPES OBSERVED IN HUMAN FIBROIDS AND PERFORM IN VITRO AND IN VIVO ASSAYS TO SELECT THE MOST PROMISING CELL LINES FOR TRANSPLANTATION INTO BABOON HOSTS. SUCCESSFUL COMPLETION OF THESE AIMS WILL ALLOW US TO APPLY FOR R01 FUNDING TO PERFORM PHASE 2 OF THE PROJECT, THE ORTHOTOPIC ALLOGRAFT ASSAYS BABOONS WITH OUR COLLABORATORS.