CELLULAR RETINOIC ACID-BINDING PROTEIN-1

维生素A，一组相关维甲酸的统称，是 对动物的正常发育和生长是必不可少的。太少了 太多会导致各种各样的生物缺陷，而且在 此外，增加酒精和各种环境造成的毒性 毒素。具有生物活性的维甲酸(RA)，其 细胞内的浓度对健康至关重要。之前的研究已经 研究表明，一种细胞维甲酸结合蛋白(CRABP)在 在维持细胞内RA浓度恒定方面起主要作用。 然而，由于CRABP在这方面是如此重要，突变和其他 极大地减少或消除这种蛋白质的操作通常是 对生物体是致命的，因此不能用于研究CRABP的功能。 这项建议的主要目标是理解积极和 CRABP基因的负调控元件及其产生的特异性变化 在这个基因中，它的表达会改变，但不会在动物身上消除。 具体地说，我们将1.确定基因的关键区域 它的调控，通过系统地删除5‘区域的部分 该基因融合到LacZ报告中，2.创造转基因小鼠，在其中 CRABP在通常不表达该蛋白的组织中表达，如 以及正常CRABP表达受阻的动物。已被占用 总之，这些研究应该说明RA和CRABP的相互作用 以及调节细胞内RA浓度的机制，以及 最终导致更好的维生素预防/治疗应用 A在人类中。

Vitamin A, the collective name for a group of related retinoids, is essential for normal development and growth in animals. Too little of too much results in a wide variety of biological defects, and in addition, increases toxicity caused by alcohol and various environmental toxins. The biologically active retinoid is retinoic acid (RA), and its concentration within cells is critical to health. Previous studies have indicated that a cellular retinoic acid-binding protein (CRABP) plays a major role in maintaining intracellular RA at a constant concentration. However, because CRABP is so vital in this regard, mutation and other manipulation that greatly reduce or eliminate this protein are generally lethal to the organism, and hence cannot be used to study CRABP function. The major goal of this proposal is to understand the positive and negative regulatory elements of CRABP gene and to create specific changes in this gene so its expression is altered but not eliminated in animals. Specifically, we will 1. determine the region of the gene essential for its regulation, by systematically deleting portions of the 5' region of the gene fused to a LacZ reporter, and 2. create transgenic mice in which CRABP is expressed in tissues normally not expressing this protein, as well as animals in which normal CRABP expression is blocked. Taken together, these studies should illustrate the interaction of RA and CRABP and the mechanisms that regulate intracellular RA concentration, and ultimately lead to better preventive/therapeutic application of vitamin A in humans.