RETINOIC ACID RECEPTOR IN DEVELOPMENT AND DISEASE

维生素A及其衍生物（类维生素A）影响多种过程， 生长、视力、形态发生和生殖。 临床上，维甲酸是 可用于治疗包括鱼鳞病在内的许多皮肤病， 牛皮癣和寻常痤疮。 它们还用于管理 皮肤淋巴瘤和其他癌症。 不良副作用包括 对母体所生胎儿畸形的一般毒性， 用维甲酸治疗痤疮。 尽管进行了深入的研究， 控制类维生素A作用的分子机制仍然不清楚。 一 在理解维甲酸作用方面取得了关键性的进展 通过分离视黄酸的特异性核受体。 的 由我们分离的受体（RAR β）在许多上皮细胞中表达， 组织，并可以预期是一个主要的介质维甲酸在 分化和增殖过程。 RAR也被 与肝细胞癌的发展有关。 我们的研究计划 阐述了类维生素A的作用机制和RAR的参与 分化与疾病。 我们将研究RAR 在人类肿瘤和正常组织中的表达，以研究 RAR β的变化发生在肿瘤中。 错误的后果 将在转基因小鼠中研究RAR β组织表达， 我们将RAR β表达导向特定组织。 这将 使我们能够检验这种受体在肝脏中的表达 可能有助于肝癌的发展，也将提供有关 RAR参与形态发生。 杂合受体，其中 配体结合结构域已与雌激素结合结构域交换 将用于开发体外模型，以分析RAR β的作用， 在细胞分化程序中。 我们也将继续我们的受体 筛选以分离其他类维生素A受体和可能的RAR受体 同种型。 我们计划的RAR β启动子分析将产生 重要的信息调节RAR β表达，并可能 指出了干扰这种机制的具体方式。 我们的研究 将深入了解这个系统中的错误如何导致疾病， 肿瘤发生 我们的研究结果将与临床使用有关， 类维生素A，应该有助于开发新的类维生素A， 消除或最小化有害副作用的治疗。

Vitamin A and its derivatives (retinoids) affect processes as diverse as growth, vision, morphogenesis and reproduction. Clinically, retinoids are useful in the treatment of many skin diseases including ichthyosis, psoriasis, and acne vulgaris. They are also used in the management of dermal lymphoma and other cancers. Undesired side effects range from general toxicity to malformations in fetuses born from mothers who have taken retinoids for acne treatment. In spite of intensive research, the molecular mechanisms which govern retinoid action have remained unclear. A crucial advance toward understanding retinoid action has been accomplished through isolation of specific nuclear receptors for retinoic acid. The receptor isolated by us (RAR epsilon) is expressed in many epithelial tissues and can be expected to be a major mediator of retinoic acid in differentiation and proliferation processes. RAR epsilon has also been implicated in hepatocellular carcinoma development. Our research plan addresses the mechanism of retinoid action and the participation of RAR epsilon in differentiation and disease. We will study RAR epsilon expression in human tumor and normal tissue to investigate how frequently changes in RAR epsilon occur in neoplasms. The consequences of erroneous RAR epsilon tissue expression will be investigated in transgenic mice in which we direct RAR epsilon expression to specific tissues. This will allow us to test the hypothesis that expression of this receptor in liver can contribute to hepatoma development and will also provide information on RAR epsilon participation in morphogenesis. Hybrid receptors in which the ligand-binding domain has been exchanged with an estrogen-binding domain will be used to develop in vitro models to analyze the roles of RAR epsilon in cellular differentiation programs. We will also continue our receptor screening to isolate other retinoid receptors and possible RAR epsilon isoforms. Our planned analysis of the RAR epsilon promoter will yield important information on the regulation of RAR epsilon expression and may point to specific ways of interfering with this mechanism. Our studies will yield insight into how errors in this system may result in disease and oncogenesis. Our research results will be relevant to the clinical use of retinoids and should be helpful for the development of new retinoids and therapies where harmful side effects are eliminated or minimized.