RETINOIC ACID RECEPTOR IN DEVELOPMENT AND DISEASE

维生素A及其衍生物(维甲酸)影响多种过程，如 生长、视觉、形态发生和繁殖。临床上，类维甲酸是 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。不良副作用的范围从 对患有先天性心脏病的母亲所生胎儿的普遍毒性 服用维甲酸治疗粉刺。尽管进行了密集的研究，但 控制维甲酸作用的分子机制仍不清楚。一个 在理解维甲酸作用方面取得了至关重要的进展 通过分离维甲酸的特定核受体。这个 我们分离的受体(RAR Epsilon)在许多上皮细胞中表达 组织中的维甲酸，有望成为维甲酸在 分化和增殖过程。RAR epsilon也被 与肝细胞癌的发展有关。我们的研究计划 阐述视黄醇的作用机制和RAR的参与 在分化和疾病中的Epsilon。我们将研究RAR epsilon 在人类肿瘤和正常组织中的表达频率调查 RAR epsilon的变化发生在肿瘤中。错误的后果 将研究RAR epsilon在转基因小鼠中的组织表达 我们将RAR epsilon的表达引导到特定的组织。这将是 允许我们测试这种受体在肝脏中表达的假设 可以促进肝癌的发展，还将提供关于 RAR epsilon参与形态发生。在杂交受体中， 配体结合域已经与雌激素结合域交换 将用于开发体外模型来分析RAR epsilon的作用 在细胞分化程序中。我们还将继续我们的受体 分离其他维甲酸受体和可能的RAR受体的筛选 异构体。我们计划对RAR epsilon启动子的分析将产生 关于RAR epsilon表达调控的重要信息和可能 指出干扰这一机制的具体方法。我们的研究 将深入了解该系统中的错误如何导致疾病和 致癌作用。我们的研究结果将与临床应用相关。 维甲酸，应该有助于开发新的维甲酸和 消除或最小化有害副作用的疗法。

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.