Maternal obesity depresses essential fatty acid transport in the placenta

点击翻译按钮获取中文摘要

Project Abstract The candidate's five-year career goal is to become an independent investigator in the areas of maternal nutrition and placental nutrient transport and metabolism. Her long-term career objective is to build a strong translational research program, utilizing appropriate animal models and human investigations to study the effect of maternal pre-pregnancy nutrition on placental growth and function, neonatal health, and the offspring's risk of future cardiovascular disease. It is becoming increasingly clear that the placenta plays a key role in the origin of adverse fetal outcomes resulting from maternal over- or under-nutrition. In keeping with this view, the placenta is an important element in the origins of adult chronic disease. The candidate has a strong scientific background in molecular biology, immunohistochemistry, primary cell culture and small and large animal surgery. She has gained expertise in fetal physiology (especially of the cardiovascular system) and is well-versed in the literature surrounding the developmental origins of health and cardiovascular disease. Additional training is required however before she can achieve her career goal of becoming an independent investigator in maternal-fetal health. The proposed training program has been designed to provide: 1) training in placental physiology and research methodologies, 2) experience in nutritional science and research methodologies and 3) in-depth training in human investigation. The Oregon Health and Science University is an ideal environment for this training. It offers its strong reputation as a leading biomedical research and training institution; the Heart Research Center is internationally recognized for its work in fetal physiology and the developmental origins of health and disease; the Oregon National Primate Research Center is internationally recognized for its translational research in pregnancy and the Oregon Clinical and Translational Research Institute is dedicated to the development of successful trainees and young investigators in translational and clinical research. One in five women who deliver in the United States is obese (body mass index (BMI) of >30 kg/m2). This condition is associated with both short- and long-term adverse consequences for mother and her baby. Such babies are at risk for developing chronic diseases including adult-onset coronary heart disease and the metabolic syndrome. Our preliminary data show that male offspring of overweight and obese mothers have lower levels of docosaehexanoic acid - a long chain polyunsaturated (LC-PUFA) derivative of essential fatty acids - than female offspring, while no differences in LC-PUFA levels exist between male and female offspring of lean women. Such deficiencies lead to neurological and vascular pathologies in the newborn. All of the essential LC-PUFA that are acquired by the fetus are actively transported across the placental barrier. The effect of maternal obesity on placental delivery of LC-PUFA to the fetus is unknown. Due to their rapid growth in utero, boys invest less in placental growth than girls and are at a greater risk of undernourishment and poor outcomes in response to stressful conditions. Maternal obesity exposes the placental-fetal unit to pro-inflammatory molecules. Inflammatory cytokines inhibit fatty acid uptake in the liver, muscle and heart. The effect of inflammatory cytokines on placental transport is not known. It is also unknown whether male fetuses and their placentas are more sensitive than females to maternal obesity and inflammation. The overall goal of this proposal is to determine the degree to which maternal obesity alters gender-specific fatty acid transport in the placenta. Studies will be conducted in our non-human primate model of maternal obesity from which we will establish the relationship between obesity and 3rd trimester placental fatty acid transport in vivo using stable isotope-labeled fatty acid tracers. Complementary studies in women will determine the degree to which maternal BMI and fetal sex alter placental lipid uptake. The roles of inflammatory cytokines in altering fatty acid uptake kinetics will be determined in placental tissue isolated from lean women with male or female offspring. These translational studies will determine the effect of maternal obesity, fetal sex and inflammatory cytokines on placental fat transport in a human population. Upon completion of the proposed studies, we will have determined 1) the degree to which maternal obesity alters uptake and transport of LC-PUFA in the late gestation non-human primate placenta, 2) the effect of fetal gender on placental LC-PUFA uptake in women at term and 3) mechanisms by which inflammatory cytokines suppress placental fatty acid uptake in vitro.