Research on development of novel pharmacological strategy for antiinflammatory drugs targeting the glucocorticoid receptor

糖皮质激素受体靶向抗炎药物新药理策略开发研究

• 批准号: 12557088
• 负责人: TANAKA Hirotoshi
• 金额: $ 7.17万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557088/
• 关键词: NUCLEAR RECEPTOR; TRANSCRIPTION FACTOR; MOLECULAR BIOLOGY; GENE EXPRESSION; PHARMACOLOGY; DRUG DEVELOPMENT; STEROID; ANTIINFLAMMATION; 炎症; 創薬; 免疫

Glucocorticoids perform these functions by binding to a cytoplasmic receptor protein glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and acts as a ligand-inducible transcription factor. As a pharmaceutics, however, glucocorticoid therapy has two opposite faces : antiinflammation/immunosuppression and metabolic side effects. Pharmacological dissociation of these therapeutic effects and side effects have been a major concern. We have developed the screening strategy for isolation of selective GR modulator (SGRM) and found that at least two classes of compounds can dissociate GR-dependent gene expression. Notably, ursodeoxycholic (UDCA) acid could exploit desirable anti-NF-kB effect with little induction of transactivational function of the GR. Effect of UDCA appears to be specific for the GR, since either PR, AR, or MR could not be translocated into the nucleus in the presence of UDCA. On the other hand, redox drugs are another candidates of SGRM. Moreover, we have identified the region in the ligand binding domain that can convey selective modulation of the receptor function. These results could be a basis for further development of SGRM.

糖皮质激素通过与细胞质受体蛋白糖皮质激素受体（GR）结合来执行这些功能，该糖皮质激素受体（GR）是核受体超家族的成员，并充当配体可诱导的转录因子。然而，作为药物，糖皮质激素治疗的面孔相反：抗炎/免疫抑制和代谢副作用。这些治疗作用和副作用的药理解离一直是一个主要问题。我们已经制定了筛选选择性GR调节剂（SGRM）的筛选策略，并发现至少两类化合物可以解离GR依赖性基因表达。值得注意的是，乌索焦胆管（UDCA）酸可以利用理想的抗NF-KB效应，而GR的反式激活功能几乎没有诱导。 UDCA的效果似乎是特定于GR的，因为在UDCA存在下，PR，AR或MR不能被转移到核中。另一方面，氧化还原药物是SGRM的另一个候选者。此外，我们已经确定了可以传达受体功能选择性调制的配体结合域中的区域。这些结果可能是SGRM进一步发展的基础。

项目成果

Toshio Homma: "Recognition of cell surface GD3 by monoclonal antibody anti-6C2 in rheumatoid arthritis synovial fluid. Expression on human T cells with transendothelial migratory activity"Arthritis Rheum. 44(2). 296-306 (2001)

Toshio Homma：“类风湿性关节炎滑液中抗 6C2 单克隆抗体对细胞表面 GD3 的识别。具有跨内皮迁移活性的人 T 细胞上的表达”关节炎大黄。

Takanori Miura: "Functional modulation of the glucocorticoid receptor and repression of NF-kB by ursodeoxycholic acid"J.Biol.Chem.. 276(50). 47371-47378 (2001)

Takanori Miura：“熊去氧胆酸对糖皮质激素受体的功能调节和 NF-kB 的抑制”J.Biol.Chem.. 276(50)。

Keiji Komura: "Aryl hydrocarbon receptor/dioxin receptor in U937 cells and human macrophages"Mol. Cell. Biochem. 226. 107-117 (2001)

Keiji Komura：“U937 细胞和人巨噬细胞中的芳基碳氢化合物受体/二恶英受体”Mol。

Jacqueline McGuire: "Definition of a Dioxin Receptor Mutant that is a Constitutive Activator of Transcription : Delineation of overlapping repression and ligand binding functions within the PAS domain"J. Biol. Chem.. 276(45). 41841-41849 (2001)

Jacqueline McGuire：“作为转录组成型激活剂的二恶英受体突变体的定义：PAS 结构域内重叠抑制和配体结合功能的描述”J.

Kiyoshi Migita, Hirotoshi Tanaka, Kensaku Okamoto, Noritada Yoshikawa, Yasufumi Ichinose, Satoshi Urayama, Satoshi Yamasaki, Hiroaki Ida, Yojiro Kawabe, Atushi Kawakami, Katsumi Eguchi: "FK506 augments glucocorticoid-mediated cyclooxygenase-2 down-regulat

Kiyoshi Migita、Hirotoshi Tanaka、Kensaku Okamoto、Noritada Yoshikawa、Yasufumi Ichinose、Satoshi Urayama、Satoshi Yamasaki、Hiroaki Ida、Yojiro Kawabe、Atushi Kawakami、Katsumi Eguchi：“FK506 增强糖皮质激素介导的环氧合酶-2 下调