Placental Carotenoids: Metabolism and Development

胎盘类胡萝卜素：代谢和发育

• 批准号: 6755112
• 负责人: LEWIS P RUBIN
• 金额: $ 27.32万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-27 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755112
• 关键词: carotenoids; cell migration; cell proliferation; clinical research; developmental nutrition; enzyme activity; flow cytometry; gene expression; genetic regulation; growth /development; hormone regulation /control mechanism; human tissue; in situ hybridization; metabolism; mother /embryo /fetus nutrition; northern blottings; nutrient intake activity; nutrition related tag; oxygenases; placental transfer; retinoids; tissue /cell culture; trophoblast; vitamin A deficiency; vitamin biosynthesis

DESCRIPTION: (Provided By Applicant) Vitamin A (retinol) supplied by the mother to her fetus is essential for normal embryogenesis, fetal development, and neonatal survival. The major source of vitamin A in mammals is oxidative cleavage of the principal dietary provitamin A carotenoid, beta-carotene (betaC). Epidemiologic and animal investigations indicate betaC and other carotenoids have pregnancy-promoting actions. An intriguing finding is that several of these properties apparently are independent of provitamin A activity. In Preliminary Studies, we have shown that placental trophoblast metabolizes betaC to retinol via the principal betaC cleavage enzyme, betaC-15,15'-dioxygenase (betaCDO). In addition, we have shown specific provitamin A and non-pro vitamin A carotenoids modulate placental growth and differentiation by actions on trophoblast gene expression. These observations have prompted the following experimental questions: (a) Does placental regulation of BetaC to retinoid metabolism serve a physiologic role akin to the placental enzymatic barrier functions which maintain intrauterine glucocorticoid and vitamin D homeostasis?; and (b) Do specific dietary carotenoids promote normal pregnancy by a combination of genomic and nongenomic events in uteroplacental target cells? This proposal addresses deficiencies of current understanding about nutritional regulation of intrauterine physiology. In order to characterize the cellular changes induced by carotenoids and to determine relevant molecular mechanisms, we will combine: well-characterized trophoblast cell culture models, systems for uniform delivery of bioavailable carotenoids over a wide concentration range, and biochemical and molecular biological analysis of carotenoid metabolism in intact cells and placental tissue. We will test the hypotheses: (a) Placental betaC-1 5,1 5'-dioxygenase (betaCDO) activity is the major (or sole) enzymatic route for fetal biotransformation to retinal, the precursor of retinoic acids. (b) Nutrient and hormonal regulation of placental betaCDO gene expression and enzyme activity modulate fetal exposure to potentially deleterious fluctuations of maternal vitamin A. We also will determine which specific carotenoids are important gestational age-dependent regulators of placental gene expression and trophoblast proliferation, migration/invasiveness and survival. Finally, we will establish whether these biological activities require carotenoid conversion to retinoids or carotenoid antioxidant activities. These studies will provide new information about potentially critical aspects of intrauterine homeostasis. Consequently, this research will increase understanding and suggest interventional strategies for vitamin A deficiency in pregnancy, a major global public health problem.

描述：（由申请人提供）母亲提供的维生素A（视黄醇） 对她的胎儿对正常的胚胎发生，胎儿发育和 新生儿生存。哺乳动物中维生素A的主要来源是氧化 主要饮食饮食中的类胡萝卜素，β-胡萝卜素（BETAC）的切割。 流行病学和动物研究表明BETAC和其他类胡萝卜素 采取促进怀孕的行动。一个有趣的发现是其中几个 这些特性显然与普罗只胺A活性无关。在 初步研究，我们表明胎盘滋养细胞代谢BETAC 通过主要BETAC裂解酶，BETAC-15,15'-二氧酶到视黄醇 （betacdo）。此外，我们已经显示了特定的普罗巴目A和非Pro维生素 类胡萝卜素通过作用调节胎盘生长和分化 滋养细胞基因表达。这些观察提示了以下 实验问题：（a）对betac对类维生素的胎盘调节 代谢发挥类似于胎盘酶壁垒的生理作用 维持子宫内糖皮质激素和维生素D的功能 稳态？ （b）做特定的饮食类胡萝卜素促进正常怀孕 结合了子宫牙靶靶中的基因组和非基因组事件 细胞？该提案解决了当前对 宫内生理学的营养调节。为了表征 类胡萝卜素诱导的细胞变化并确定相关的分子 机制，我们将结合：特征良好的滋养细胞培养 模型，用于在宽宽的系统上均匀交付的系统 浓度范围以及生化和分子生物学分析 完整细胞和胎盘组织中的类胡萝卜素代谢。我们将测试 假设：（a）胎盘betac-1 5,1 5'-二氧酶（betacdo）活动是 用于视网膜的胎儿生物转化的主要（或唯一）酶促途径 视黄酸的前体。 （b）胎盘的营养和荷尔蒙调节 Betacdo基因表达和酶活性调节胎儿暴露于 母体维生素A的潜在有害波动。我们也将 确定哪些特定类胡萝卜素是重要的妊娠年龄 胎盘基因表达和滋养细胞增殖的调节剂， 迁移/侵入性和生存。最后，我们将确定是否 生物活动需要类胡萝卜素转化为类视黄素或类胡萝卜素 抗氧化活性。这些研究将提供有关有关的新信息 宫内稳态的潜在关键方面。因此，这个 研究将提高理解并提出介入的策略 维生素A缺乏怀孕，这是一个主要的全球公共卫生问题。