Vitamin A Supplementation and Retinol Metabolism in the Neonatal Period

 描述（由申请方提供）：已知维生素A（VA）对出生后未成熟器官系统的生长和发育以及免疫力的建立至关重要，但新生儿的VA代谢几乎未进行研究。目前，世界卫生组织（WHO）在VA缺乏症仍然是公共卫生问题的低收入国家推广对6个月以上幼儿补充VA，作为降低幼儿死亡率和改善全球健康的一种手段。然而，对新生儿（小于6个月的婴儿）补充VA是有争议的，世卫组织尚未制定针对该年龄组的政策。我们的目标是使用具有成本效益和经过充分验证的动物模型来深入了解VA在以非补充或补充剂量提供时如何在全身吸收和运输。我们将使用两种不同的方案，直接补充VA的新生儿和间接补充通过添加VA的母亲的饮食，以测试我们的中心假设，即：直接补充VA的新生儿，通过口服VA补充，和间接补充VA，通过增加母亲的饮食VA，将显着，但不同的，改变全身视黄醇动力学的新生儿。此外，根据我们的初步研究，我们认为这些给药途径会有所不同。我们的目标是提供关于新生大鼠模型中视黄醇吸收、运输和组织分布的基本新知识， 基于3 H-视黄醇动力学分析和数学建模的全身方法。因为我们的研究结果，从以前的授权期间已经表明，肝外组织中的乳糜微粒（CM）携带的新吸收的VA的清除的重要性，我们将集中在CM VA代谢和它的运输从肠道和肝外组织以及肝脏的摄取。我们还获得了初步证据，视黄酸（RA），最活跃的代谢物的视黄醇，可能会驱动视黄醇进入这些肝外器官。因此，在目标1.1中，我们将使用3 H-视黄醇示踪动力学和数学建模研究对直接补充VA的新生儿进行研究，与油安慰剂相比，VA的剂量与幼儿的剂量相似。男性和女性新生儿均将纳入设计中。目的1.2还将讨论RA在确定新生儿全身VA动力学方面的重要性。目的2将解决间接补充维生素A后，在新生儿中的视黄醇动力学，通过添加到母亲的饮食，其牛奶中的维生素A浓度将增加。通过实现这两个目标，我们将获得基本的新信息，这些信息可以为未来关于人类新生儿补充VA的政策提供信息。由于VA补充剂是一种实用，低成本的营养干预措施，如果我们的研究获得积极的结果，它们可以很容易地转化为临床试验。

 DESCRIPTION (provided by applicant): Vitamin A (VA) is known to be essential for the postnatal growth and development of immature organ systems and establishment of immunity, yet VA metabolism in neonates is virtually unstudied. Currently, the World Health Organization (WHO) promotes VA supplementation of young children >6 months of age in low-income countries where VA deficiency is still a public health problem, as a means to reduce young child mortality and improve global health. However, VA supplementation of neonates (infants < 6 mo of age) is controversial and WHO has not established a policy for this age group. Our goal is to use a cost-efficient and well-validated animal model to learn, in depth, how VA, when provided either at non-supplemental or supplemental doses, is absorbed and trafficked throughout the body. We will use two different protocols, direct VA supplementation of neonates and indirect supplementation through addition of VA to the maternal diet, to test our central hypothesis, namely: Direct VA supplementation of neonates, through oral VA supplementation, and indirect VA supplementation, through increased maternal dietary VA, will be significantly, but differently, alter whole-body retinol kinetics in neonates. Moreover, we believe based on our preliminary studies that these routes of administration will differ. Our goal is to provide fundamental new knowledge on retinol absorption, trafficking, and tissue distribution in a neonatal rat model using a whole-body approach that is based on 3H-retinol kinetic analysis and mathematical modeling. Because our results from the previous grant period have suggested the importance of extrahepatic tissues in the clearance of newly absorbed VA carried in chylomicrons (CM), we will focus on CM VA metabolism and on its transport from the intestine and uptake by extrahepatic tissues as well as by the liver. We also have obtained preliminary evidence that retinoic acid (RA), the most active metabolite of retinol, may drive retinol into these extrahepati organs. Therefore, in aim 1.1 we will conduct a study using 3H-retinol tracer kinetics and mathematical modeling studies of neonates that have been supplemented directly with VA, given at a dose what resembles that which has been administered to young children, compared to an oil placebo. Both male and female neonates will be included in the design. Aim 1.2 will also address the importance of RA in determining whole-body VA kinetics in neonates. Aim 2 will address retinol kinetics in the neonate after indirect supplementation through addition of VA to the diet of the mother, whose milk VA concentration will be augmented. By conducting these two aims, we will gain fundamental new information that could inform future policies regarding VA supplementation in human neonates. Since VA supplementation is a practical, low-cost nutritional intervention, if positive results are obtained from our research they could be readily translated into clinical trials.