Selective Modulation of Thyroid Receptor Action

描述(由申请人提供)：核受体(NRs)调节人类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、维甲酸和前列腺素的受体。NR功能的选择性调节是NR配体设计中的一个新兴概念。虽然取得了进展，但许多概念却鲜为人知。许多TH行动将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，降低血浆胆固醇、甘油三酯和脂蛋白(A)水平。然而，这些好处被有害的影响所抵消，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阻断TH是可取的，但目前通过抑制TH的产生来阻断TH的起效很慢。因此，识别选择性的TR调制器(STRM)是很重要的。我们使用结构-活性图谱和TRX-射线晶体结构设计：(I)选择性TRR调节剂(STRM)，它优先结合TRbeta形式，可能是治疗肥胖和血脂紊乱的原型药物；以及(Ii)新型TRR拮抗剂和部分激动剂。初步研究表明，这些配体可能还具有潜在的有用的选择性性质，包括细胞对单个启动子元件的摄取、激活和抑制的差异，以及它们的活性受辅助激活因子和辅助抑制因子调节的能力。在拟议的研究中，我们计划检查一系列配体的性质，以更好地了解它们的活性。我们将确定单个STRM对以下方面的影响：(I)TR构象；(Ii)在无细胞条件下和细胞内与辅因子的相互作用；(Iii)单个TRR的激活功能；(Iv)在模型启动子处的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，以提供单个和组合特征的轮廓，这些特征最终可能被用于合理设计具有比纯激动剂或拮抗剂更理想的轮廓的配体。这项研究将扩大我们对选择性的tr调节在特定的和一般的NR作用中的理解。

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.