FUNCTIONS OF RETINOL BINDING PROTEIN

一般认为，大多数组织会以视黄醇的形式获得维生素A 由其特定的血清运输蛋白-视黄醇结合传递 蛋白质(RBP)。RBP是视黄醇在体内的唯一运输蛋白 发行量。RBP提供的视黄醇在细胞内被氧化成 维甲酸，它调节维生素A反应基因的表达，或 视觉神经所需的视黄醛。因此，假定RBP正在播放 在调节维生素A的生物学作用中起着至关重要的作用。 然而，有几条RBP不依赖的途径可供细胞 可能获得所需的维甲酸(维生素A及其类似物)。这些措施包括 维甲酸通过循环的直接输送， 视黄酸酯在乳胶粒和可能的其他物质中的输送 脂蛋白，两者对完全水溶性葡萄糖醛酸苷的摄取 视黄醇和维甲酸从循环，并通过摄取 循环中存在的类胡萝卜素转化为类维A酸。 尽管这些传递途径通常被认为是次要的 阳萎，我们对转甲状腺激素(TTR)缺失的小鼠的研究表明 这种观念可能并不正确。这些突变的小鼠，它们完全是 健康和有生育能力，血浆视黄醇-RBP水平非常低 这相当于一只极度缺乏维生素A的动物。 这些研究表明，RBP可能不是维持 生物体的健康。这项提议的目标是产生RBP- 并利用缺陷小鼠来探讨这种动物的生理作用 并确定RBP是否在任何 细胞过程。 我们将通过有针对性地破坏RBP来产生RBP缺陷小鼠 基因，使用我们之前使用的ES细胞技术创建 Ttr-零小鼠品系。我们计划了两个战略。第一个将生成 完全缺乏RBP的小鼠；第二种将产生无法 在肝脏或脂肪组织(RBP的两个主要部位)合成RBP 综合)。这些突变体将被用于详细研究 RBP条件下类维甲酸的摄取、转运和代谢 缺乏症。 我们研究的具体目的是：目的1.建立RBP缺陷小鼠 通过有针对性的整合并表征这些动物的表型 和目标2.调查饮食中类维甲酸的摄取和传递 这些突变小鼠体内的组织。

It is generally believed that most tissues acquire vitamin A as retinol delivered by its specific serum transport protein, retinol-binding protein (RBP). RBP is the sole transport protein for retinol in the circulation. Retinol delivered by RBP is oxidized within cells to retinoic acid, which regulates vitamin A-responsive gene expression, or to retinaldehyde which is needed in vision. Thus, RBP is assumed to play an essential role in mediating the biological actions of vitamin A. However, there are several RBP-independent pathways through which cells might acquire needed retinoid (vitamin A and its analogs). These include the direct delivery of retinoic acid through the circulation, the delivery of retinyl esters in chylomicrons and possibly other lipoproteins, the uptake of fully water-soluble glucuronides of both retinol and retinoic acid from the circulation, and through the uptake and conversion of carotenoids present in the circulation to retinoids. Although these delivery pathways are usually considered to be of minor impotence, our studies of the transthyretin (TTR)-null mouse suggest that this notion may not be correct. These mutant mice, which are fully healthy and fertile, have very low levels of plasma retinol-RBP, levels that are comparable to those of an extremely vitamin A-deficient animal. These studies imply that RBP may not be essential for maintaining the health of the organism. The goal of this proposal is to generate RBP- defective mice and to use this animal to explore the physiological role of serum RBP and to determine if RBP plays an indispensable role in any cellular process. We will generate an RBP-defective mouse by targeted disruption of the rbp gene, using the ES cell technology we previously employed to create the TTR-null mouse strain. We plan two strategies. The first will generate mice that totally lack RBP; the second will yield animals unable to synthesize RBP in the liver or adipose tissue (the two major sites of RBP synthesis). These mutants will be used for a detailed study of the uptake, transport and metabolism of retinoid under conditions of RBP deficiency. The specific aims of our study are: Aim 1. To generate RBP-deficient mice by targeted integration and to characterize these animals phenotypically and Aim 2. To investigate retinoid uptake from the diet and its delivery to tissues in these mutant mice.