FUNCTIONS OF RETINOL BINDING PROTEIN

一般认为，大多数组织获得维生素A的视黄醇 通过其特异性血清转运蛋白，视黄醇结合蛋白 蛋白（RBP）。RBP是视网膜中唯一的视黄醇转运蛋白， 流通由RBP递送的视黄醇在细胞内被氧化， 视黄酸，调节维生素A反应基因表达，或 到视觉所需的视黄醇。因此，RBP被认为是发挥 在介导维生素A的生物学作用中起重要作用。 然而，有几种不依赖于RBP的途径， 可能会获得所需的类维生素A（维生素A及其类似物）。这些包括 通过循环直接输送视黄酸， 在乳糜微粒和可能的其他微粒中释放视黄基酯 脂蛋白，吸收完全水溶性的葡萄糖醛酸苷， 视黄醇和视黄酸从循环，并通过摄取 以及将循环中存在的类胡萝卜素转化为类视色素。 虽然这些传递途径通常被认为是次要的， 阳痿，我们对甲状腺素运载蛋白（TTR）缺失小鼠的研究表明， 这种观念未必正确。这些突变小鼠， 健康和有生育能力，血浆视黄醇-RBP水平非常低， 与极度缺乏维生素A的动物的维生素A含量相当。 这些研究表明，RBP可能不是维持 有机体的健康。本提案的目标是产生RBP- 缺陷小鼠，并利用这种动物来探索生理作用 血清RBP，并确定RBP是否在任何 细胞过程 我们将通过靶向破坏rbp来产生rbp缺陷小鼠， 基因，使用我们以前用于创建 TTR无效小鼠品系。我们制定了两个战略。第一个将产生 完全缺乏RBP的小鼠;第二种将产生无法 在肝脏或脂肪组织中合成RBP（RBP的两个主要部位 合成）。这些突变体将用于详细研究 RBP条件下类维生素A的摄取、转运和代谢 缺陷 本研究的具体目标是：目标1。为了产生RBP缺陷小鼠 通过靶向整合并表征这些动物的表型 目标2研究饮食中类维生素A的摄取及其释放 突变小鼠的组织中。

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.