Project Grant F31HL184908

PATHOLOGICAL EFFECTS OF MATERNAL BETA-THALASSEMIA ON FETAL DEVELOPMENT - PROJECT SUMMARY B -THALASSEMIA REPRESENTS A SIGNIFICANT GLOBAL PUBLIC HEALTH BURDEN, AFFECTING MORE THAN 1.5% OF THE POPULATION AND 40,000 LIVE BIRTHS ANNUALLY.1,2 PATIENTS WITH THIS CONDITION PRESENT WITH ANEMIA, INEFFECTIVE ERYTHROPOIESIS, AND PERTURBED IRON HOMEOSTASIS, RESULTING IN EXCESSIVE IRON ABSORPTION AND OVERLOAD,3 WHICH IS THE MAJOR CAUSE OF MORBIDITY AND MORTALITY. IN B-THALASSEMIA, IRON HOMEOSTASIS IS PERTURBED BY THE EXCESSIVE RELEASE OF ERYTHROFERRONE FROM THE BONE MARROW, WHICH INAPPROPRIATELY SUPPRESSES THE CRITICAL IRON REGULATORY HORMONE HEPCIDIN. INAPPROPRIATELY LOW HEPCIDIN RESULTS IN IRON LOADING IN TISSUES SUCH AS THE HEART, MUSCLE, AND BRAIN, CAUSING TISSUE DYSFUNCTION.5-7 TREATMENT OF B-THALASSEMIA HAS IMPROVED GREATLY IN THE PAST FEW DECADES THROUGH BLOOD TRANSFUSIONS AND IRON CHELATION THERAPY, AND MORE WOMEN WITH THIS CONDITION ARE ABLE TO BECOME PREGNANT. HOWEVER, THESE PREGNANCIES ARE AT HIGHER RISK OF COMPLICATIONS SUCH AS INTRAUTERINE GROWTH RESTRICTION, LOW BIRTH WEIGHT AND PRETERM BIRTH, FOR REASONS THAT ARE NOT WELL ELUCIDATED. IMPORTANTLY, DURING PREGNANCY BLOOD TRANSFUSION REQUIREMENTS ARE INCREASED WHILE CHELATION THERAPY IS HALTED TO AVOID TERATOGENIC EFFECTS IN THE DEVELOPING FETUS, INCREASING MATERNAL IRON LOADING.8-11 IN THESE AIMS, USING MOUSE MODELS, WE WILL INVESTIGATE THE EFFECT OF MATERNAL B-THALASSEMIA ON PATHOPHYSIOLOGICAL CHANGES DURING PREGNANCY AND FETAL DEVELOPMENT, AS WELL AS PATHWAYS MEDIATING ADVERSE FETAL AND POSTNATAL OUTCOMES. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT MATERNAL IRON LOADING AND ANEMIA IN B-THALASSEMIA CONTRIBUTES TO CHANGES IN EPIGENETIC REGULATION IN FETAL TISSUES SENSITIVE TO IRON-LOADING AND HYPOXIA. IN AIM 2, WE WILL UNCOVER THE CONNECTION BETWEEN B-THALASSEMIA AND ALTERATIONS IN TRANSCRIPTOMIC PATHWAYS IN THE EMBRYONIC BRAIN; AND AIM 3 WILL ADDRESS THE PERSISTENCE OF CHANGES POSTNATALLY, AND ASSOCIATED BEHAVIORAL CONSEQUENCES. UNDERSTANDING THE PATHOPHYSIOLOGICAL CHANGES IN MATERNAL AND FETAL IRON AND OXYGEN METABOLISM IN THALASSEMIC PREGNANCIES AND HOW THEY PERTURB FETAL AND POSTNATAL DEVELOPMENT WILL INFORM FUTURE STUDIES AIMED AT TAILORING PRENATAL CARE TO IMPROVE MATERNAL AND FETAL OUTCOMES.