Selective Modulation of Thyroid Receptor Action

描述（由申请人提供）：核受体（NR）调节人类的许多医学重要过程，包括甲状腺（TH）和类固醇激素、维生素D、类维生素A和肾上腺素的受体。NR功能的选择性调节是NR配体设计中的一个新兴概念。虽然取得了进展，但许多概念仍不为人所知。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，促进体重减轻，降低胆固醇、甘油三酯和脂蛋白（a）的血浆水平。然而，TH益处被有害影响抵消，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阻断TH是可取的，但目前通过抑制TH产生的阻断作用起效缓慢。因此，鉴定选择性TR调节剂（STRM）是重要的。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），其优先结合TR β形式，并且可以是用于治疗肥胖和脂质紊乱的原型药物;和（ii）新型TR拮抗剂和部分激动剂。初步研究表明，这些配体可能有进一步的潜在有用的选择性，包括在细胞摄取，激活和抑制个别启动子元件的差异，和他们的活动的能力，以调节辅激活子和辅阻遏物。在拟议的研究中，我们计划检查配体光谱的性质，以更好地了解它们的活动。我们将确定单个STRM对以下方面的影响：（i）TR构象;（ii）无细胞条件下和细胞中TR与辅因子的相互作用;（iii）单个TR激活功能;（iv）模型启动子处TR介导的基因表达;以及（v）完整细胞中的基因表达谱。所获得的信息将被整合，以提供个人和组合的功能，可以最终开发的配体的合理设计更理想的配置文件比纯激动剂或拮抗剂的配置文件。这项研究将扩大我们的理解，选择性TR调制的具体和NR的行动一般。

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.