Maternal obesity depresses essential fatty acid transport in the placenta

应聘者描述(由申请人提供)：应聘者的五年职业目标是成为一名母亲营养和胎盘营养运输和代谢领域的独立研究员。她的长期职业目标是建立一个强大的转化性研究计划，利用适当的动物模型和人体调查来研究孕妇孕前营养对胎盘生长和功能、新生儿健康以及后代未来心血管疾病风险的影响。越来越清楚的是，胎盘在母亲营养过度或营养不足导致的不良胎儿结局的起源中起着关键作用。与这一观点一致的是，胎盘是成人慢性病起源的重要因素。应聘者在分子生物学、免疫组织化学、原代细胞培养和大小动物外科方面都有很强的科学背景。她在胎儿生理学(特别是心血管系统)方面获得了专业知识，并精通关于健康和心血管疾病发育起源的文献。然而，在她实现成为母婴健康独立调查员的职业目标之前，还需要进行额外的培训。拟议的培训计划旨在提供：1)胎盘生理学和研究方法方面的培训，2)营养科学和研究方法方面的经验，以及3)人类调查方面的深入培训。俄勒冈健康与科学大学是这种培训的理想环境。作为领先的生物医学研究和培训机构，俄勒冈州国家灵长类动物研究中心享有很高的声誉；心脏研究中心因其在胎儿生理学以及健康和疾病的发育起源方面的工作而受到国际认可；俄勒冈州国家灵长类动物研究中心因其怀孕期间的翻译研究而得到国际认可，俄勒冈州临床和翻译研究所致力于培养翻译和临床研究方面的成功实习生和年轻研究人员。在美国分娩的女性中，有五分之一患有肥胖症(体重指数为30公斤/平方米)。这种情况与母亲及其婴儿的短期和长期不良后果有关。这些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，超重和肥胖母亲的雄性后代的二十二碳己酸--一种必需脂肪酸的长链多不饱和(LC-PUFA)衍生物--的水平低于雌性后代，而瘦身女性的雄性和雌性后代的LC-PUFA水平没有差异。这些缺陷会导致新生儿的神经和血管病理。胎儿获得的所有必需的LC-PUFA都会主动地通过胎盘屏障运输。母亲肥胖对LC-PUFA胎盘分娩胎儿的影响尚不清楚。由于在子宫内的快速生长，男孩在胎盘生长方面的投资比女孩少，因此在应对压力条件下营养不良和不良结局的风险更大。母亲肥胖使胎盘-胎儿单位暴露于促炎分子。炎性细胞因子抑制肝脏、肌肉和心脏对脂肪酸的摄取。炎性细胞因子对胎盘转运的影响尚不清楚。男性胎儿和他们的胎盘是否比女性对母亲的肥胖和炎症更敏感也是未知的。这项提案的总体目标是确定母亲肥胖在多大程度上改变了胎盘中特定性别的脂肪酸运输。我们将在母体肥胖的非人灵长类动物模型中进行研究，在此基础上，我们将使用稳定的同位素标记脂肪酸示踪剂，建立肥胖与体内晚期胎盘脂肪酸运输的关系。对女性的补充研究将确定母亲体重指数和胎儿性别对胎盘脂肪摄取的影响程度。炎性细胞因子在改变脂肪酸摄取动力学中的作用将在从有男性或女性后代的瘦弱女性身上分离出来的胎盘组织中确定。这些翻译研究将确定母体肥胖、胎儿性别和炎性细胞因子对人类人群胎盘脂肪运输的影响。研究完成后，我们将确定1)妊娠晚期非人类灵长类胎盘中肥胖对LC-PUFA摄取和转运的影响程度，2)胎儿性别对足月胎盘LC-PUFA摄取的影响，3)炎性细胞因子体外抑制胎盘脂肪酸摄取的机制。 与公共健康相关：美国产后妇女的肥胖率为五分之一，这与母亲和孩子的严重健康后果有关。众所周知，由于母亲肥胖导致发育期间胎儿营养不良，会使孩子在以后的生活中患心血管疾病的风险更高。拟议的研究将帮助我们了解妊娠期肥胖如何改变胎盘营养物质从母亲到孩子的转移，以及这如何影响新生儿营养。

DESCRIPTION (provided by applicant): 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-PUFAlevels 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. PUBLIC HEALTH RELEVANCE: The prevalence of obesity in women who give birth in the US is 1 in 5, which is associated with severe health consequences for both mother and child. Poor fetal nutrition during development due to maternal obesity is known to put the child at a higher risk of cardiovascular disease in later life. The proposed studies will help us understand how obesity during pregnancy alters the placental transfer of nutrients from mother to child and how this impacts neonatal nutrition.