Maternal obesity depresses essential fatty acid transport in the placenta

孕妇肥胖会抑制胎盘中必需脂肪酸的转运

• 批准号: 8643321
• 负责人: Perrie F O'Tierney-Ginn
• 金额: $ 24.97万
• 依托单位: METROHEALTH MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643321
• 关键词: 5' -AMP-activated protein kinase; Acids; Adolescent; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arachidonic Acids; Area; Biomedical Research; Birth; Blood Vessels; Body mass index; C-reactive protein; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Child; Chronic Disease; Clinical Research; Coronary heart disease; Data; Depressed mood; Development; Diet; Dietary Essential Fatty Acid; Disease; Elderly; Environment; Epidemic; Essential Fatty Acids; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female; Fetal Development; Fetus; Future; Gender; Gene Expression; Goals; Growth; Health; Health Care Costs; Health Sciences; Heart Research; Human; Immunohistochemistry; In Vitro; Incidence; Indium; Inflammation; Inflammatory; Institution; Interleukin-8; Interleukins; Investigation; Japanese Population; Kinetics; Label; Lead; Life; Lipids; Literature; Liver; Macaca; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; Molecular Biology; Monkeys; Mothers; Myocardium; Neonatal; Neurologic; Newborn Infant; Nutrient; Obesity; Oleic Acids; Operative Surgical Procedures; Oregon; Outcome; Overweight; Pathology; Perinatal; Physiology; Placenta; Play; Population; Pregnancy; Prenatal Nutrition; Prevalence; Primary Cell Cultures; Primates; Property; Protein Kinase Inhibitors; Research; Research Institute; Research Methodology; Research Personnel; Research Training; Risk; Role; Scientist; Stable Isotope Labeling; Stearic Acids; Third Pregnancy Trimester; Tissues; Tracer; Training; Training Programs; Translational Research; Tumor Necrosis Factor-alpha; United States; Universities; Woman; Work; abstracting; adverse outcome; boys; cardiovascular disorder risk; career; cytokine; design; experience; fatty acid transport; fetal; fetus nutrition; girls; high risk; in utero; in vivo; male; mother nutrition; nonhuman primate; nutrition; offspring; placental transfer; pregnant; programs; protein kinase inhibitor; rapid growth; receptor; response; sensor; sex; translational study; uptake

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.

项目摘要 候选人的五年职业目标是成为孕产妇营养领域的独立调查员 以及胎盘营养物质的运输和代谢。她的长期职业目标是建立一个强大的翻译 研究计划，利用适当的动物模型和人类调查，研究产妇的影响， 孕前营养对胎盘生长和功能、新生儿健康以及后代未来风险的影响 心血管疾病越来越清楚的是，胎盘在妊娠的起源中起着关键作用。 母亲营养过剩或营养不足导致的不良胎儿结局。根据这一观点，胎盘是 成人慢性病的起源中的一个重要因素。 候选人在分子生物学，免疫组织化学，初级免疫学和免疫组织化学方面有很强的科学背景。 细胞培养和小型和大型动物手术。她获得了胎儿生理学方面的专业知识（特别是 心血管系统），并精通围绕健康的发展起源和 心血管疾病然而，在她实现职业目标之前， 成为母胎健康的独立调查员拟议的培训方案已 旨在提供：1）胎盘生理学和研究方法的培训，2）营养学方面的经验， 科学和研究方法和3）在人类调查的深入培训。俄勒冈州卫生和 理科大学是这种培训的理想环境。作为领先的生物医学领域， 研究和培训机构;心脏研究中心是国际公认的胎儿 生理学和健康与疾病的发展起源;俄勒冈州国家灵长类动物研究中心 是国际公认的转化研究在怀孕和俄勒冈州临床和转化 研究所致力于培养成功的学员和年轻的研究人员， 转化和临床研究。 在美国，五分之一的分娩妇女肥胖（体重指数（BMI）>30 kg/m2）。这 这种情况与母亲及其婴儿的短期和长期不良后果有关。等 婴儿有患慢性疾病的风险，包括成人型冠心病和 代谢综合征我们的初步数据显示，超重和肥胖母亲的男性后代具有较低的 二十二碳六烯酸（一种必需脂肪酸的长链多不饱和（LC-PUFA）衍生物）的水平比 雌性后代，而瘦女性的雄性和雌性后代之间的LC-PUFA水平没有差异。等 缺乏导致新生儿神经和血管病变。所有必需的LC-PUFA， 由胎儿获得的蛋白质被主动转运穿过胎盘屏障。母亲肥胖对 LC-PUFA向胎儿的胎盘递送是未知的。由于他们在子宫内的快速增长，男孩在胎盘上的投资较少。 这些儿童的生长速度比女孩快，在应对压力条件时营养不良和结果不佳的风险更大。 母亲肥胖使胎盘-胎儿单位暴露于促炎分子。炎性细胞因子抑制脂肪 肝脏、肌肉和心脏的酸吸收。炎性细胞因子对胎盘转运的影响尚不清楚。是 也不知道男性胎儿及其胎盘是否比女性对母体肥胖更敏感， 炎症这项提案的总体目标是确定母亲肥胖改变的程度， 胎盘中的性别特异性脂肪酸转运。 研究将在我们的非人灵长类动物模型的母亲肥胖，我们将 建立肥胖与孕晚期胎盘脂肪酸转运之间的关系， 同位素标记的脂肪酸示踪剂。对妇女的补充研究将确定产妇 BMI和胎儿性别改变胎盘脂质摄取。炎性细胞因子在改变脂肪酸摄取中的作用 将在从具有雄性或雌性后代的瘦女性分离的胎盘组织中测定动力学。这些 转化研究将确定母体肥胖、胎儿性别和炎性细胞因子对 胎盘脂肪运输的研究 在完成拟议的研究后，我们将确定1）产妇死亡的程度 肥胖改变妊娠晚期非人灵长类胎盘中LC-PUFA的摄取和转运，2） 胎儿性别对足月妇女胎盘LC-PUFA摄取的影响和3） 炎性细胞因子在体外抑制胎盘脂肪酸摄取。