Selective Modulation of Thyroid Receptor Action

描述（由申请人提供）：核受体（nr）调节人类许多医学上重要的过程，包括甲状腺（TH）和类固醇激素、维生素D、类维生素a和前列腺素的受体。NR功能的选择性调制是NR配体设计中的一个新兴概念。虽然取得了进展，但人们对许多概念知之甚少。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，促进体重减轻，降低血浆胆固醇、甘油三酯和脂蛋白水平(a)。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。它是理想的阻断甲状腺机能亢进，但目前的阻断通过抑制甲状腺激素的产生是缓慢的起病。因此，识别选择性TR调制器（strm）是很重要的。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（STRMs），它优先结合trβ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的潜在有用的选择特性，包括细胞摄取的差异，单个启动子元件的激活和抑制，以及它们的活性受辅激活因子和辅抑制因子调节的能力。在提出的研究中，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，TR与辅因子的相互作用；（iii）单个TR激活功能；（iv） tr介导的模型启动子基因表达；(v)完整细胞的基因表达谱。所获得的信息将被整合，以提供个体和组合特征的概况，这些特征可能最终被用于合理设计配体，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异性和NR作用的选择性TR调制的理解。

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.