Cell cycle and diseases

细胞周期与疾病

• 批准号: 13043012
• 负责人: KOHSAKA Hitoshi
• 金额: $ 47.74万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13043012/
• 关键词: rheumatoid arthritis; enhropathy; animal models; cell cycle; 治療; サイクリン依存性キナーゼ阻害因子; 急性腎不全; 慢性関節リウマチ

Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit. CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) mice with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti-type II collagen (Cll) antibodies and proliferative responses to Cll were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to Cll were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed CIA. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA not by suppressing lymphocyte function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis

关节内基因转移细胞周期蛋白依赖性激酶抑制剂（CDKI），以抑制滑膜细胞周期已显示出疗效，在治疗类风湿性关节炎（RA）的动物模型。CDKIs还通过非CDKIs依赖性途径调节免疫功能。因此，全身施用抑制的小分子。CDK可能改善关节炎。为了解决这个问题，测试了已知在临床上耐受用于治疗癌症的阿伏西地（flavopiridol）以及新合成的CDK 4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制人和小鼠滑膜成纤维细胞的增殖而不诱导凋亡。在体内，用阿伏西地治疗胶原诱导的关节炎（CIA）小鼠抑制了滑膜增生和关节破坏，同时维持了抗II型胶原（Cll）抗体的血清浓度和对Cll的增殖反应。即使在治疗性给药时，治疗也是有效的。给药小鼠在给药终止后发生关节炎。因此，对Cll的免疫应答未受损。相同的治疗改善了由K/BxN血清转移到淋巴细胞缺陷小鼠诱导的关节炎。类似地，CDK 4/6选择性抑制剂抑制CIA。两种小分子CDK抑制剂均能有效治疗RA动物模型，而不是通过抑制淋巴细胞功能。我们相信smCDK抑制剂有望成为一类新的抗风湿药物，可抑制类风湿发病的不同阶段

项目成果

抗関節リウマチ活性を有する物質のスクリーニング方法及び評価方法。

具有抗风湿活性的物质的筛选方法和评价方法。

• 发表时间: 2006

Kohsaka H, Nasu K, Nonomura Y, Miyasaka N.: "Treatment of Arthritis with Cyclin-dependent Kinase Inhibitor Gene"Jpn J Clin Immunol. 23(6). 550-552 (2001)

Kohsaka H，Nasu K，Nonomura Y，Miyasaka N.：“用细胞周期蛋白依赖性激酶抑制剂基因治疗关节炎”Jpn J Clin Immunol。

Nishio J, Kohsaka H, et al.: "Development of TCRB CDR3 length repertoire of human lymphocytes"Int Immunol. 16(3). 423-431 (2004)

Nishio J、Kohsaka H 等人：“人类淋巴细胞的 TCRB CDR3 长度库的开发”IntImmunol。

Positional effect of amino acid replacement on peptide antigens for the increased IFN-gamma production from CD4 T cells.

氨基酸置换对肽抗原的位置影响，以增加 CD4 T 细胞的 IFN-γ 产量。

• 发表时间: 2005
• 期刊: Allergol Int 54(1)
• 作者: Liu T;Kohsaka H;Suzuki M;Takagi R;Hashimoto K;Uemura Y;Ohyama H;Matsushita S
• 通讯作者: Matsushita S

Terada Y., Inoshita S., Hanada S.et al.: "Hyperosmolality activates Akt and regulates apoptosis in renal tubular cells"Kidney International. 60(2). 553-567 (2001)

Terada Y.、Inoshita S.、Hanada S.等人：“高渗透压激活 Akt 并调节肾小管细胞凋亡”Kidney International。