Project Grant R16HD116702

ROLES OF PLACENTAL MITOCHONDRIA IN THE VICIOUS CYCLE OF DIABETES AND PREGNANCY - PROPOSAL ABSTRACT TYPE II DIABETES MELLITUS (T2D) WITH INCREASING PREVALENCE REPRESENTS A MAJOR BURDEN FOR HEALTH AND CARE SYSTEM AND INDIVIDUALS. HOWEVER, THE ROOT CAUSE OF T2D HAS NOT BEEN UNDERSTOOD COMPLETELY. RECENT HUMAN EPIDEMIOLOGICAL STUDIES INDICATE THAT GESTATIONAL DIABETES MELLITUS (GDM) PREDISPOSES TYPE 2 DIABETES (T2D) AND OTHER METABOLIC DISEASES IN OFFSPRING, RESULTING IN A VICIOUS CYCLE OF DIABETES AND PREGNANCY TRANSGENERATIONALLY. THEREFORE, DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASES (DOHAD) MAY PROVIDE A NEW ANGLE IN THE STUDIES OF METABOLIC DISEASES INCLUDING T2D. THE DUAL ROLES OF BNIP3 IN MEDIATING MITOPHAGY AND LIPID METABOLISM SUGGEST THAT THE DELETION OF BNIP3 IN TROPHOBLAST CELLS IS EXPECTED TO IMPAIR PLACENTAL MITOCHONDRIAL FUNCTION, LIPID CATABOLISM, AND THUS, NEGATIVELY AFFECTING MATERNAL METABOLIC ADAPTATIONS TO PREGNANCY AND LEADING TO THE DEVELOPMENT OF GDM. WE PROPOSE THAT BNIP3 MAY PLAY A CRITICAL ROLE IN THE PROCESS OF PLACENTAL DEVELOPMENT AND CONSEQUENT PROGRAMMING OF T2D IN OFFSPRING. IN THIS APPLICATION, WE HYPOTHESIZE THAT BNIP3 MEDIATED PLACENTAL MITOPHAGY PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF GDM AND TROPHOBLAST SPECIFIC KNOCKOUT OF BNIP3 IN PREGNANT MICE WILL CAUSE MATERNAL GDM AND PREDISPOSE T2D IN OFFSPRING THROUGH PLACENTAL PROGRAMMING. CONTINUING OUR PREVIOUS STUDY, WE WILL CONFIRM THE IMPAIRED PLACENTAL MITOPHAGY IN GDM WOMEN WHICH IS MEDIATED BY BNIP3 (AIM 1), THEN WE WILL INVESTIGATE THE ROLE OF BNIP3 DEPENDENT MITOPHAGY PATHWAY IN THE DEVELOPMENT OF GDM IN A MOUSE MODEL WITH TROPHOBLAST SPECIFIC KNOCKOUT OF BNIP3 (AIM 2). USING THIS UNIQUE MOUSE GDM MODEL, WE WILL INVESTIGATE THE ONSET AND PROGRESSION OF T2D IN OFFSPRING (AIM 3). TAKEN TOGETHER, THE PROPOSED STUDIES, FOR THE FIRST TIME, MODEL THE VICIOUS CYCLE BETWEEN MATERNAL GDM AND GDM PREDISPOSED ADULT METABOLIC DISEASES BY MANIPULATING THE PLACENTAL MITOPHAGY BUT NOT INTERFERING WITH OTHER MATERNAL ORGANS, AND THUS, PROVIDING POWERFUL PLATFORM IN THE MECHANISTIC STUDIES ON GDM AND T2D, HELPING DEVELOP NOVEL MEANS FOR THE PREVENTION AND TREATMENT OF THESE DISEASES, AND BREAKING THE VICIOUS CYCLE OF DIABETES AND PREGNANCY.