Project Grant F32HD123180

DEFINING STRUCTURE-FUNCTION INTERPLAY IN OVIDUCT SMOOTH MUSCLE - PROJECT SUMMARY/ABSTRACT THE OVERALL OBJECTIVE OF THIS STUDY IS TO IDENTIFY AND CHARACTERIZE KEY DYNAMICS OF TUBAL TRANSPORT IN BOTH MOUSE AND HUMAN OVIDUCTS. TO ACCOMPLISH THIS, I WILL LEVERAGE HIGHLY INNOVATIVE, HIGH RESOLUTION VOLUMETRIC IMAGING METHODS AND DOWNSTREAM COMPUTATIONAL ANALYSES PIONEERED BY MY LAB THAT ALLOW FOR PRECISE, 4D RESOLUTION OF CROSS-SPECIES TUBAL DYNAMICS. TUBAL FACTOR IS ESTIMATED TO BE IMPLICATED IN 30-40% OF ALL FEMALE INFERTILITY CASES; HOWEVER, DESPITE ITS PREVALENCE, OVIDUCTAL FUNCTION REMAINS A SEVERELY UNDERSTUDIED AREA OF REPRODUCTIVE BIOLOGY. MANY STUDIES RELY ON MOUSE MODELS TO ELUCIDATE HUMAN OVIDUCT FUNCTION, BUT HOW CLOSELY THE MOUSE OVIDUCT RECAPITULATES THE STRUCTURE AND FUNCTION OF THE HUMAN OVIDUCT (FALLOPIAN TUBE) IS UNKNOWN, PRESENTING A SIGNIFICANT BARRIER TO TRANSLATIONAL DISCOVERY. PRELIMINARY STUDIES IN THE MOUSE OVIDUCT REVEAL REGION-SPECIFIC LUMINAL ARCHITECTURE AND CILIA DISTRIBUTION, IN ADDITION TO A NOVEL 'GATE-LIKE' REGION OF FUNCTIONAL CONSTRICTION IN THE ISTHMUS-AMPULLARY JUNCTION. BY UTILIZING STATE-OF-THE-ART VOLUMETRIC IMAGING AND QUANTITATIVE ANALYSES, THIS STUDY AIMS TO COMPREHENSIVELY COMPARE THE ARCHITECTURE AND CELL TYPE DISTRIBUTION THROUGHOUT THE MOUSE AND HUMAN OVIDUCTS, PROVIDING THE FIRST COMPLETE 'MAP' OF THE HUMAN OVIDUCT WITH THE ADDITIONAL SPECIFIC GOAL OF FURTHER CHARACTERIZING IN MICE AND IDENTIFYING IN HUMANS THE CRITICAL 'GATE-LIKE' DYNAMIC STRUCTURE FOR THE FIRST TIME. IN ADDITION TO QUANTITATIVE STRUCTURAL CHARACTERIZATIONS, THIS PROJECT WILL ALSO INVESTIGATE CROSS-SPECIES DYNAMIC FUNCTIONS OF THE OVIDUCT THAT REMAIN UNKNOWN. FOR SUCCESSFUL TUBAL TRANSPORT, THE COORDINATED, DYNAMIC ACTIONS OF MOTILE CILIA AND SMOOTH MUSCLE (SM) ARE REQUIRED TO GENERATE DIRECTIONAL MOVEMENT OF THE OOCYTES AND EMBRYOS FROM THE OVARY TO THE UTERUS. WHILE CILIARY FUNCTION IN THE OVIDUCT HAS BEEN LINKED TO CILIOPATHY- ASSOCIATED INFERTILITY AND EXTENSIVELY STUDIED BY OUR LAB, THE ROLE AND REGULATION OF SM, WHICH HAS ALSO BEEN GENETICALLY IMPLICATED IN SOME REPRODUCTIVE DISORDERS, IN THE OVIDUCT REMAINS POORLY UNDERSTOOD. PRELIMINARY STUDIES INDICATE REGION-SPECIFIC DIFFERENCES IN SM FUNCTION TO AID IN OOCYTE/EMBRYO TRANSFER. FURTHER, RECENT CLINICAL DATA SUGGEST THAT MODULATING SM FUNCTION THROUGH THE HORMONAL REGULATOR OXYTOCIN IMPACTS IN VITRO FERTILIZATION SUCCESS, THOUGH THE FUNCTION OF OXYTOCIN IN THE OVIDUCT HAS NOT YET BEEN STUDIED. THIS PROPOSAL WILL PERFORM THE FIRST IN-DEPTH QUANTITATIVE CHARACTERIZATION OF SM DYNAMICS IN THE MOUSE AND HUMAN OVIDUCTS AND IDENTIFY SM REGULATORY PATHWAYS WITH TRANSLATIONAL IMPACT. NEW DISCOVERIES GAINED FROM THIS PROPOSED PROJECT WILL BE EXTREMELY TRANSLATIONALLY RELEVANT, CONTRIBUTING BOTH TO OUR BASIC UNDERSTANDING OF CROSS-SPECIES OVIDUCTAL FUNCTION AND IDENTIFICATION OF REGULATORY PATHWAYS OF TUBAL TRANSPORT, A CRITICAL AND PATHOLOGICALLY RELEVANT REPRODUCTIVE PROCESS.