Vitamin A Supplementation and Retinol Metabolism in the Neonatal Period

 说明(申请人提供)：众所周知，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是必不可少的，但对新生儿的VA代谢几乎没有研究。目前，世界卫生组织(世卫组织)在低收入国家促进对6个月大的幼儿补充维生素A，在这些国家，维生素A缺乏仍然是一个公共卫生问题，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(婴儿和婴儿6个月大)补充维生素A是有争议的，世卫组织还没有为这一年龄段制定政策。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是如何在非补充或补充剂量下在体内被吸收和贩运的。我们将使用两种不同的方案，即新生儿直接补充VA和通过在母亲饮食中添加VA间接补充，来检验我们的中心假设，即：通过口服VA直接补充新生儿VA，以及通过增加母亲饮食VA间接补充VA，将显著但不同地改变新生儿的全身视黄醇动力学。此外，根据我们的初步研究，我们认为这些给药途径将有所不同。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。 一种基于~3H-视黄醇动力学分析和数学模型的全身方法。由于我们在上一次赠款期间的结果表明，肝外组织在清除乳糜粒(CM)携带的新吸收的VA方面具有重要意义，因此我们将重点关注CM VA的代谢及其从肠道的转运，以及肝外组织和肝脏的吸收。我们还获得了初步证据，视黄醇最活跃的代谢物维甲酸(RA)可能推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~3H-视黄醇示踪动力学和数学模型对直接补充VA的新生儿进行研究，给药剂量与给幼儿的剂量相似，并与油安慰剂进行比较。男婴和女婴都将包括在设计中。AIM 1.2还将讨论RA在确定新生儿全身VA动力学中的重要性。目标2将通过在母亲的饮食中添加维生素A来解决间接补充后新生儿中的视黄醇动力学问题，母亲的乳中维生素A浓度将会增加。通过实施这两个目标，我们将获得基本的新信息，这些信息可能为未来有关人类新生儿补充VA的政策提供信息。由于维生素A补充剂是一种实用、低成本的营养干预措施，如果从我们的研究中获得积极的结果，它们很容易转化为临床试验。

 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.