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: 8257957
• 负责人: Perrie F O'Tierney-Ginn
• 金额: $ 8.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257957
• 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; 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; public health relevance; rapid growth; receptor; response; sensor; sex; translational study; uptake

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.

描述（由申请人提供）：候选人的五年职业目标是成为孕产妇营养和胎盘营养转运和代谢领域的独立研究者。她的长期职业目标是建立一个强大的转化研究项目，利用适当的动物模型和人体研究来研究母亲孕前营养对胎盘生长和功能、新生儿健康以及后代未来患心血管疾病风险的影响。越来越清楚的是，胎盘在母亲营养过剩或营养不足导致胎儿不良结局的根源中发挥着关键作用。根据这一观点，胎盘是成人慢性疾病起源的重要因素。 该候选人在分子生物学、免疫组织化学、原代细胞培养以及小型和大型动物手术方面拥有深厚的科学背景。她拥有胎儿生理学（尤其是心血管系统）方面的专业知识，并且精通有关健康和心血管疾病的发育起源的文献。然而，在她实现成为母胎健康独立调查员的职业目标之前，她还需要接受额外的培训。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，3）人体研究方面的深入培训。俄勒冈健康与科学大学是进行此类培训的理想环境。它作为领先的生物医学研究和培训机构享有盛誉；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获得国际认可；俄勒冈国家灵长类动物研究中心因其妊娠转化研究而获得国际认可，俄勒冈临床和转化研究所致力于培养转化和临床研究方面成功的学员和年轻研究人员。 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）。这种情况会对母亲和婴儿造成短期和长期的不良后果。这些婴儿有患慢性疾病的风险，包括成人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六烯酸（一种必需脂肪酸的长链多不饱和（LC-PUFA）衍生物）水平低于雌性后代，而雄性和雌性之间的 LC-PUFA 水平不存在差异瘦女人的后代。这种缺陷会导致新生儿出现神经和血管病变。胎儿获得的所有必需的 LC-PUFA 都会主动转运穿过胎盘屏障。母亲肥胖对胎盘向胎儿输送 LC-PUFA 的影响尚不清楚。由于男孩在子宫内生长迅速，因此对胎盘生长的投入比女孩少，并且在应对压力条件时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。炎症细胞因子抑制肝脏、肌肉和心脏的脂肪酸摄取。炎症细胞因子对胎盘转运的影响尚不清楚。目前还不清楚男性胎儿及其胎盘是否比女性对母亲肥胖和炎症更敏感。该提案的总体目标是确定孕产妇肥胖改变胎盘中性别特异性脂肪酸转运的程度。 我们将在我们的非人类灵长类母亲肥胖模型中进行研究，通过该模型，我们将使用稳定同位素标记的脂肪酸示踪剂建立肥胖与妊娠第三期胎盘脂肪酸体内转运之间的关系。对女性的补充研究将确定母亲体重指数和胎儿性别改变胎盘脂质摄取的程度。炎性细胞因子在改变脂肪酸摄取动力学中的作用将在从具有男性或女性后代的瘦女性中分离的胎盘组织中确定。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胎盘脂肪转运的影响。 完成拟议的研究后，我们将确定 1) 孕产妇肥胖改变妊娠晚期非人灵长类胎盘中 LC-PUFA 的摄取和转运的程度，2) 胎儿性别对胎盘 LC-PUFA 摄取的影响足月女性；3) 体外炎症细胞因子抑制胎盘脂肪酸摄取的机制。 公共卫生相关性：在美国分娩的女性中，肥胖的患病率为五分之一，这对母亲和孩子都会造成严重的健康后果。众所周知，由于母亲肥胖而导致胎儿发育期间营养不良，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怀孕期间的肥胖如何改变胎盘从母亲到孩子的营养转移以及这如何影响新生儿的营养。