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

基本信息

批准号：
8847576
负责人：
Perrie F O'Tierney-Ginn
金额：
$ 23.46万
依托单位：
METROHEALTH MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847576
关键词：
5&apos -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 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-1 Interleukin-8 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 Nutritional Science Obesity Oleic Acids Operative Surgical Procedures Oregon Outcome Overweight Pathology Perinatal Perinatal mortality demographics 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

项目摘要

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.

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研究者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强大的翻译团队研究计划，利用适当的动物模型和人体调查来研究母体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，胎盘在胎儿的起源中起着关键作用。母亲营养过剩或营养不足导致胎儿不良结局。根据这一观点，胎盘是成人慢性疾病起源的一个重要因素。候选人在分子生物学、免疫组织化学、初级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（尤其是胎儿生理学）心血管系统），并且精通有关健康和发展起源的文献心血管疾病。然而，在她实现职业目标之前，还需要接受额外的培训成为母婴健康领域的独立研究者。拟议的培训计划已旨在提供：1）胎盘生理学和研究方法方面的培训，2）营养方面的经验科学和研究方法；3) 人类调查的深入培训。俄勒冈州健康与科学大学是这种培训的理想环境。它作为领先的生物医学领域享有盛誉研究和培训机构；心脏研究中心因其在胎儿方面的工作而获得国际认可生理学以及健康和疾病的发育起源；俄勒冈国家灵长类动物研究中心因其妊娠转化研究以及俄勒冈州临床和转化研究而获得国际认可研究所致力于培养成功的实习生和年轻的研究人员转化和临床研究。在美国，五分之一的分娩女性患有肥胖症（体重指数 (BMI) > 30 kg/m2）。这这种情况会对母亲和婴儿造成短期和长期的不良后果。这样的婴儿有患慢性疾病的风险，包括成人发病的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的死亡率较低二十二碳六烯酸（一种必需脂肪酸的长链多不饱和 (LC-PUFA) 衍生物）的含量女性后代的 LC-PUFA 水平不存在瘦女性的男性和女性后代之间的差异。这样的缺陷会导致新生儿出现神经和血管病变。所有必需的 LC-PUFA 胎儿获得的物质主动转运穿过胎盘屏障。产妇肥胖对产妇的影响胎盘向胎儿输送 LC-PUFA 的情况尚不清楚。由于男孩在子宫内生长迅速，对胎盘的投资较少生长发育低于女孩，并且因应对压力条件而面临更大的营养不良和不良后果的风险。母亲肥胖会使胎盘-胎儿单位暴露于促炎分子。炎症细胞因子抑制脂肪肝脏、肌肉和心脏的酸吸收。炎症细胞因子对胎盘转运的影响尚不清楚。这是还不清楚男性胎儿及其胎盘是否比女性对母亲肥胖更敏感炎。该提案的总体目标是确定孕产妇肥胖改变的程度胎盘中性别特异性脂肪酸运输。研究将在我们的非人类灵长类动物母亲肥胖模型中进行，我们将从中使用稳定的方法建立肥胖与妊娠第三期胎盘脂肪酸体内转运之间的关系同位素标记的脂肪酸示踪剂。对女性的补充研究将确定母亲的影响程度 BMI 和胎儿性别改变胎盘脂质摄取。炎症细胞因子在改变脂肪酸摄取中的作用将在从具有男性或女性后代的瘦女性身上分离的胎盘组织中测定动力学。这些转化研究将确定母亲肥胖、胎儿性别和炎症细胞因子对人群中胎盘脂肪的运输。完成拟议的研究后，我们将确定 1) 母亲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 摄取的影响以及 3) 机制炎症细胞因子在体外抑制胎盘脂肪酸的摄取。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fatty acid transporter expression and regulation is impaired in placental macrovascular endothelial cells in obese women.

肥胖女性胎盘大血管内皮细胞中脂肪酸转运蛋白的表达和调节受损。

DOI：
发表时间：
2019-03
期刊：
影响因子：
0
作者：
Yang, Xiaohua;Glazebrook, Patricia;Ranasinghe, Geraldine C;Haghiac, Maricela;Calabuig;Minium, Judi;O'Tierney
通讯作者：
O'Tierney

Neonatal fatty acid profiles are correlated with infant growth measures at 6 months.

新生儿脂肪酸谱与 6 个月时婴儿的生长指标相关。