COREPRESSORS AND NEGATIVE REGULATION BY THYROID HORMONE

描述（摘自申请人摘要）： 甲状腺激素受体（TR）与甲状腺激素反应元件结合 在基因的调控区中，TRE刺激或抑制基因的表达。 转录。TR在配体存在或不存在的情况下结合， 三碘甲状腺原氨酸（T3）。在缺乏配体的情况下，TR抑制转录 受T3正调控的基因。非配体依赖性 阻遏由一类称为辅阻遏物的蛋白质介导， 包括NCoR和SMRT，其在T3不存在时结合TR。TR也 对由一个或多个配体负调控的基因表现出配体非依赖性作用， 甲状腺激素在这些负性TRE中，TRE增强了细胞中的转录。 不存在配体。这些影响尚不清楚，但似乎是 也是由共阻遏物家族成员介导的。的目标 这些研究是（1）表征辅阻遏物对 甲状腺激素负调控基因;（2）识别和 表征NCoR亚型;和（3）确定共阻遏物如何 与特定TR复合物相互作用。在这些研究中，我们将重点关注 辅阻遏物和TR-β-2之间的相互作用，TR-β-2是一种TR亚型， 可能在负调节中发挥独特的作用。此外，突变TR， 临床上发现于甲状腺抵抗综合征患者 激素（RTH）将用于表征TR之间的相互作用， 辅阻遏物同种型。这些信息将使我们能够进一步定义 甲状腺激素抵抗和甲状腺激素 行动，这将揭示人类甲状腺功能减退症的基础上， 甲状腺机能亢进此外，了解TRs如何调节基因表达， 在没有配体的情况下的转录将提供进一步的了解， 基因调控的机制。该项目将 由罗纳德科恩博士在弗雷德里克博士的指导下进行 Wondisford，在Beth Israel的甲状腺单位和内分泌部门 女执事医疗中心Wondisford博士为以下方面做出了重大贡献： 对控制负性的分子机制的理解 TSH和TRH基因的调节。也有众多的调查人员 在内分泌部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，并将提供一个基础 科恩医生转型为独立调查员

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.