Project Grant R41HD113465

THERAPEUTIC TARGETING OF FKBP51 FOR THE PREVENTION OF STRESS-INDUCED PRETERM BIRTH - IN THE UNITED STATES, ONE IN TEN BABIES IS BORN PREMATURELY. THE EARLIER IN PREGNANCY A BABY IS BORN, THE MORE LIKELY THEY WILL HAVE AN EXTENDED HOSPITAL STAY, AS WELL AS SERIOUS HEALTH COMPLICATIONS SUCH AS RESPIRATORY DISTRESS SYNDROME, NECROTIZING ENTEROCOLITIS, DEAFNESS, VISION PROBLEMS AND CEREBRAL PALSY. MATERNAL STRESS IS A WELL-ESTABLISHED RISK FACTOR FOR PRETERM BIRTH, AND RECENT STUDIES USING A MOUSE MODEL OF MATERNAL STRESS HIGHLIGHT THE ROLE OF A STRESS RESPONSE PROTEIN, FKBP51, IN PROMOTING PRETERM BIRTH. PRIOR WORK DEMONSTRATES THAT STRESS BOOSTS FKBP51 EXPRESSION. CONSEQUENTLY, FKBP51 BINDS TO PROGESTERONE RECEPTORS IN DECIDUAL CELLS AT THE MATERNAL-FETAL INTERFACE, REDUCING PROGESTERONE RECEPTOR ACTIVITY IN THE NUCLEUS, RESULTING IN THE FUNCTIONAL WITHDRAWAL OF PROGESTERONE THAT TRIGGERS LABOR AND BIRTH IN HUMANS. IMPORTANTLY, THIS NOVEL MOLECULAR PATHWAY CAN BE BLOCKED BY 15-DEOXY-12,14-PROSTAGLANDIN J2 (15DPGJ2), RESTORING THE ACTIVITY OF PROGESTERONE RECEPTORS IN VITRO AND IN VIVO. THUS, THERAPEUTIC TARGETING OF FKBP51 HAS GREAT POTENTIAL AS A SAFE AND EFFECTIVE STRATEGY TO PREVENT PRETERM BIRTH. BECAUSE THERE EXIST NO PHARMACOLOGICAL STRATEGIES FOR THE PREVENTION OF PRETERM BIRTH, DARE BIOSCIENCE, IN COLLABORATION WITH THE UNIVERSITY OF SOUTH FLORIDA, AIMS TO RIGOROUSLY DEMONSTRATE THE FEASIBILITY OF TARGETING FKBP51 TO IMPROVE OBSTETRIC TREATMENT OPTIONS FOR WOMEN. WORK IN AIM 1 IS FOCUSED ON VALIDATING FKBP51 AS A NOVEL DRUG TARGET USING CLINICALLY-RELEVANT HUMAN DECIDUAL CELL CULTURE MODELS, SELECTING A THERAPEUTIC STRATEGY THAT COMBINES 15DPGJ2 WITH DELIVERY OF A PROGESTIN, AND EVALUATING THE DOWNSTREAM BIOLOGICAL EFFECTS OF TREATMENT. THE FOCUS OF AIM 2 IS TO DEMONSTRATE THE IN VIVO SAFETY AND EFFICACY OF 15DPGJ2 PLUS PROGESTIN COMBINATION THERAPY FOR PREGNANCY MAINTENANCE IN A PREVIOUSLY VALIDATED MATERNAL STRESS INDUCED MOUSE MODEL OF PRETERM BIRTH. THE GOAL IS TO DEMONSTRATE A STATISTICALLY SIGNIFICANT INCREASE IN GESTATIONAL LENGTH BY TREATMENT(S) IN STRESSED ANIMALS VS. UNTREATED STRESSED CONTROLS. THIS PROJECT HAS SIGNIFICANT TRANSLATIONAL AND COMMERCIAL POTENTIAL BECAUSE IT WILL PROVIDE THE NECESSARY PROOF-OF-CONCEPT DATA TO ADVANCE A TREATMENT STRATEGY TO PHASE II IND-ENABLING STUDIES.