Cell cycle and diseases

细胞周期与疾病

基本信息

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

项目摘要

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

细胞周期蛋白依赖性激酶抑制剂（CDKI）抑制滑膜细胞循环的关节内基因转移已显示出在治疗类风湿关节炎动物模型（RA）方面的功效。 CDKIS还通过CDKINTEPENT途径调节免疫功能。因此，全身施用抑制的小分子。 CDK可能会改善关节炎。为了解决这个问题，已知在临床治疗癌症上耐受耐受的Alvocidib（黄素寡醇），还测试了新合成的CDK4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制了人和小鼠滑膜成纤维细胞的增殖，而无需诱导凋亡。在体内，用Alvocidib治疗胶原蛋白诱导的关节炎（CIA）小鼠抑制了滑膜增生和关节破坏，而血清抗型II胶原蛋白（CLL）抗体的浓度则保持了对CLL的增殖反应。即使治疗治疗也是有效的。治疗后治疗后患有关节炎。因此，对CLL的免疫反应没有受损。 K/BXN血清转移到淋巴细胞缺陷小鼠引起的相同治疗可以改善关节炎。同样，CDK4/6选择性抑制剂抑制了CIA。两个小分子（SM）CDK抑制剂均在不抑制淋巴细胞功能的RA动物模型中有效治疗动物模型。我们认为，SMCDK抑制剂作为一种新类别的抗风湿药有望，抑制类风湿病的不同阶段

项目成果

期刊论文数量（96）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclin-dependent kinase 4/6 directly modulates expression of rheumatoid inflammatory mediators in retinoblastoma protein-dependent and independent pathways

细胞周期蛋白依赖性激酶 4/6 直接调节视网膜母细胞瘤蛋白依赖性和独立通路中类风湿炎症介质的表达

DOI：
发表时间：
期刊：
Arthritis Rheum. (in press)
影响因子：
0
作者：
Nonomura Y;Nagasaka K;Hagiyama H;Sekine C;Nanki T;Tamamori-Adachi M;Miyasaka N;Kohsaka N.
通讯作者：
Kohsaka N.

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。