COREPRESSORS AND NEGATIVE REGULATION BY THYROID HORMONE

描述(摘自申请人的摘要)： 甲状腺激素受体(TRs)与甲状腺激素反应元件结合 (Tres)在基因的调节区刺激或抑制基因 抄写。TRS在存在或不存在配体的情况下结合， 三碘甲腺原氨酸(T3)。在缺乏配体的情况下，TRs抑制转录 受T3正向调控的基因。非配基依赖 抑制是由一类被称为共抑制物的蛋白质介导的， 包括NCoR和SMRT，它们在没有T3的情况下绑定TR。TRS还 对受A基因负调控的基因表现出非配体依赖的效应 甲状腺激素。在这些负的TRE中，TRs增强了转录。 没有配基。这些影响的定义不那么明确，但似乎是 也是由共同抑制者家族的成员调解的。的目标 这些研究是：(1)表征共抑制物对细胞周期的影响 甲状腺激素负调控基因；(2)鉴定和鉴定 确定NCoR异构体的特征；以及(3)确定共抑制物如何 与特定的TR复合体相互作用。在这些研究中，我们将重点放在 共抑制物与TR-β-2之间的相互作用 可能在负面调控中起着明显的作用。此外，突变的TRs， 临床上发现于甲状腺抵抗综合征患者 激素(RTH)将被用来描述TRs和TRs之间的相互作用。 共抑制物异构体。这些信息将使我们能够进一步定义 甲状腺激素抵抗的机制及甲状腺激素 行动，这将揭示人类甲状腺功能减退和 甲亢。此外，对转录激活剂如何调控基因的理解 在没有配基的情况下进行转录将提供对 基因调控的一般机制。这个项目将是 由罗纳德·科恩博士在弗雷德里奇博士的指导下完成 Wondisford，在Beth以色列的甲状腺单位和内分泌部 女执事医疗中心。Wondisford博士在以下方面做出了重大贡献 对负离子调控分子机制的认识 TSH和TRH基因的调控。也有无数的调查人员 在内分泌科和周围的哈佛医学院 对转录调控感兴趣的社区。这将提供 一个理想的环境来完成这个项目，并将提供基础 科恩博士向独立调查员的转变。

DESCRIPTION (Taken from the applicant's Abstract): Thyroid hormone receptors (TRs) bind to thyroid hormone response elements (TREs) in the regulatory regions of genes to stimulate or inhibit gene transcription. TRs bind in the presence or absence of ligand, triiodothyronine (T3). In the absence of ligand, TRs repress transcription of genes that are positively regulated by T3. Ligand-independent repression is mediated by a class of proteins termed co-repressors, including NCoR and SMRT, which bind TR in the absence of T3. TRs also exhibit ligand-independent effects on genes negatively regulated by a thyroid hormone. One these negative TREs, TRs enhance transcription in the absence of ligand. These effects are less well defined, but appear to be mediated by members of the co-repressor families, as well. The goals of these studies are (1) to characterize the effects of co-repressors on genes negatively regulated by thyroid hormone; (2) to identify and characterize NCoR isoforms; and (3) to determine how co-repressors interact with specific TR complexes. In these studies, we will focus on the interactions between co-repressors and TR-beta-2, a TR isoform that may play a distinct role in negative regulation. In addition, mutant TRs, found clinically in patients with syndromes of resistance to thyroid hormone (RTH) will be used to characterize interactions between TRs and co-repressor isoforms. This information will allow us to define further mechanisms underlying thyroid hormone resistance and thyroid hormone action, which will shed light on the basis of human hypothyroidism and hyperthyroidism. Moreover, an understanding of how TRs regulate gene transcription in the absence of ligand will provide further insight into the mechanisms of gene regulation in general. This project will be performed by Dr. Ronald Cohen under the guidance of Dr. Fredric Wondisford, in the Thyroid Unit and Endocrine Division of the Beth Israel Deaconess Medical Center. Dr. Wondisford has made major contributions to the understanding of the molecular mechanisms governing negative regulation of the TSH and TRH genes. There are also numerous investigators in the Endocrine Division and the surrounding Harvard Medical School community with interests in transcriptional regulation. This will provide an ideal environment to complete this project, and will provide a basis for Dr. Cohen's transition to an independent investigator.