The role of b-carotene in maternal-fetal nutrition

说明（申请人提供）：母亲的营养状况是胎儿发育生长的关键因素。维生素A是发育中的胚胎所必需的营养物质，它依赖于母体循环的维生素A（或类维生素A）来满足其需要。的确，胚胎维生素a缺乏和过量会导致胎儿畸形，这在发展中世界和工业化国家都是一个严重的问题。人类主要依靠维生素A原类胡萝卜素作为维生素A的来源。胡萝卜素是最具特征的维生素A前体，也是人类饮食中最丰富的维生素A营养素。-胡萝卜素- 15,15 '-加氧酶（CMO I）和-胡萝卜素- 9,10 '-加氧酶（CMO II）两种酶已被确定为-胡萝卜素裂解特定双键从而形成维生素a的催化剂。目前，-胡萝卜素在母胎营养中的作用尚不清楚。来自文献的证据表明，这种类胡萝卜素可能是发育组织中维生素A的重要局部来源。我们计划通过使用缺乏CMO I和视黄醇结合蛋白（RBP）的小鼠来解决这个关键的生物学问题，RBP是循环中视黄醇的唯一特异性载体。我们还将使用缺乏低密度脂蛋白受体（LDLr）或B类清道夫受体（SR-BI）或脂蛋白脂肪酶（LPL）的小鼠来研究这些脂质代谢的关键参与者在促进-胡萝卜素的母胎转移中的作用。提出了三个具体目标：(1)确定在小鼠发育过程中调节CMO I和CMO II表达的因素。(2)确定-胡萝卜素是否是胚胎合成类维生素A的替代来源。(3)探讨母胎屏障（即胎盘和卵黄囊）对-胡萝卜素的吸收和加工机制。这些研究将最终扩大我们对母胎营养和饮食对胚胎发育的贡献的认识，从而为怀孕期间适当的饮食习惯提供新的见解。这些研究对人类健康有重大影响，因为它们的目的是减少与母亲摄入维生素等微量营养素异常有关的胎儿畸形发生率。

DESCRIPTION (provided by applicant): The nutritional status of the mother is a key factor for the development and growth of the fetus. Vitamin A is an essential nutrient for the developing embryo, which depends on maternal circulating vitamin A (or retinoids) to fulfill its needs. Indeed, embryonic vitamin A-deficiency as well as -excess result in fetal malformations, representing a serious problem in both the developing world and the industrialized countries. Humans rely mainly on provitamin A carotenoids as a source of vitamin A. ¿-carotene is the best-characterized vitamin A precursor and the most abundant supply of this nutrient in the human diet. Two enzymes, ¿-carotene-15, 15'-oxygenase (CMO I) and ¿-carotene-9, 10'-oxygenase (CMO II), have been identified as catalysts for the cleavage of specific double bonds of ¿-carotene, resulting in the formation of vitamin A. At present, the role of ¿-carotene in maternal-fetal nutrition is not well understood. Evidences from the literature suggest that this carotenoid may be an important, localized source of vitamin A for the developing tissues. We plan to address this crucial biological question by using mice lacking both CMO I and retinol-binding protein (RBP), the sole specific carrier for retinol in the circulation. We will also use mice lacking low density lipoprotein receptor (LDLr) or class B scavenger receptor (SR-BI) or lipoprotein lipase (LPL) to investigate the role of these key players of the lipid metabolism in facilitating the maternal-fetal transfer of ¿-carotene. Three specific aims are proposed: (1) To identify factors that modulate the expression of CMO I and CMO II during mouse development. (2) To determine whether ¿-carotene is an alternative source of vitamin A for embryonic synthesis of retinoids. (3) To investigate the mechanisms of uptake and processing of ¿-carotene by the maternal-fetal barrier (i.e., placenta and yolk sac). These studies will ultimately expand our knowledge of maternal-fetal nutrition and dietary contribution to embryonic development, thus providing new insight into appropriate dietary practices during pregnancy. These studies have a significant impact on human health, since they aim at reducing the incidence of fetal malformations associated with an abnormal maternal intake of micronutrients, such as vitamins.