Selective Modulation of Thyroid Receptor Action

甲状腺受体作用的选择性调节

• 批准号: 6837596
• 负责人: JOHN D BAXTER
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837596
• 关键词: cell line; chemical structure function; chromatin immunoprecipitation; cofactor; conformation; gel mobility shift assay; gene expression; gene expression profiling; ligands; nuclear receptors; protein structure function; receptor expression; thyroid hormones; transfection

DESCRIPTION (provided by applicant): Nuclear receptors (NRs) regulate numerous medically important processes in humans and include receptors for thyroid (TH) and steroid hormones, vitamin D, retinoids and prostaglandins. Selective modulation of NR function is an emerging concept in NR ligand design. While there is progress, many concepts are poorly understood. Many TH actions would have medical utility in reducing cardiovascular disease risk. TH stimulates metabolism, promotes weight loss, and lowers plasma levels of cholesterol, triglycerides, and lipoprotein (a). However, TH benefits are offset by deleterious influences, including effects on heart that include life-threatening tachycardia and arrhythmia. It is desirable to block TH in hyperthyroidism, but current blockade by inhibiting TH production is slow in onset. Thus, it is important to identify selective TR modulators (STRMs). We used structure-activity profiling and TR X-ray crystal structures for designing: (i) selective TR modulators (STRMs) that preferentially bind the TRbeta-form, and may be prototype drugs for treating obesity and lipid disorders; and (ii) novel TR antagonists and partial agonists. Preliminary studies indicate that these ligands could have further potentially useful selective properties, including differences in cell uptake, activation and suppression of individual promoter elements, and abilities of their activities to be regulated by coactivators and corepressors. In the proposed studies we plan to examine properties of a spectrum of ligands to better understand their activities. We will determine effects of individual STRMs on: (i) TR conformation; (ii) TR interactions with cofactors in cell-free conditions and in cells; (iii) individual TR activation functions; (iv) TR-mediated gene expression at model promoters; and (v) gene expression profiles in intact cells. The information obtained will be integrated to provide profiles for individual and combinatorial features that may be ultimately exploited for rational design of ligands with more desirable profiles than either pure agonists or antagonists. This study will expand our understanding of selective TR modulation in specific and NR action in general.

描述（由申请人提供）：核受体 (NR) 调节人体中许多重要的医学过程，包括甲状腺 (TH) 和类固醇激素、维生素 D、类视黄醇和前列腺素的受体。 NR 功能的选择性调节是 NR 配体设计中的一个新兴概念。尽管取得了一些进展，但许多概念仍知之甚少。许多 TH 行动在降低心血管疾病风险方面具有医疗效用。 TH 刺激新陈代谢，促进减肥，并降低血浆胆固醇、甘油三酯和脂蛋白 (a) 水平。然而，TH 的益处被有害影响所抵消，包括对心脏的影响，包括危及生命的心动过速和心律失常。在甲状腺功能亢进症中需要阻断 TH，但目前通过抑制 TH 产生进行的阻断起效缓慢。因此，识别选择性 TR 调节剂 (STRM) 非常重要。我们使用结构-活性分析和 TR X 射线晶体结构来设计：（i）选择性 TR 调节剂（STRM），优先结合 TRbeta 形式，可能是治疗肥胖和脂质疾病的原型药物； (ii)新型TR拮抗剂和部分激动剂。初步研究表明，这些配体可能具有进一步潜在有用的选择性特性，包括细胞摄取、单个启动子元件的激活和抑制的差异，以及它们的活性受共激活子和辅阻遏物调节的能力。在拟议的研究中，我们计划检查一系列配体的特性，以更好地了解它们的活性。我们将确定各个 STRM 对以下方面的影响： (i) TR 构象； (ii) TR在无细胞条件下和细胞内与辅因子的相互作用； (iii) 单独的 TR 激活函数； (iv) TR介导的模型启动子基因表达； (v) 完整细胞中的基因表达谱。所获得的信息将被整合以提供个体和组合特征的概况，这些特征最终可用于配体的合理设计，其具有比纯激动剂或拮抗剂更理想的概况。这项研究将扩大我们对特定选择性 TR 调节和一般 NR 作用的理解。