Investigation for the possibility of CaMKII activity modulation for the therapeutic optical in rheumatoid arthritis

CaMKII 活性调节用于类风湿性关节炎治疗光学的可能性的研究

• 批准号: 18591116
• 负责人: KAWAKAMI Atsushi
• 金额: $ 2.49万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591116/
• 关键词: FLS; RA; CaMKII; Akt; apoptosis; HL-60; citrullination; PADI4; 関節リウマチ(RA); 蛋白シトルリン化; 細胞分化; 関節リウマチ; CIA; 滑膜線維芽細胞; TRAIL依存性アポトーシス; 治療ターゲット

The remarkable proliferation as well as apoptosis resistance are crucial for rheumatoid arthritis (RA). Among them, we have focused on the importance of PI3K/Akt pathway, and in the current 2 years, we have tried to investigate the role of CaMKII pathway. FLS in culture expressed CaMKII γ and δ, especially δ isoform. The addition of CaMKII chemical inhibitor, KN93, significantly augmented apoptosis sensitivity of FLS in response to TRAIL and anti-Fas antibody. The additional experiment showed that CaMKII-induced phenomena of apoptosis sensitivity are mediated through Akt. CaMKII is an enzyme that is activated by Ca ion influx. Ca ion influx also activates PADI, which is an essential enzyme for post-transcriptional mechanism of peptide citrullination. Post-transcriptional mechanism of peptide citrullination is thought to be crucial for anti-CCP antibodies production in patients with RA, a RA-specific autoantibodies. However, we could not detect the citrullinated peptides in cultured FLS in response to Ca ion influx, pro-inflammatory cytoltines or pro-apoptotic stimuli. Thus, we conducted the experiment by the use of human cell line, HL-60. HL-60 expressed CaMKII γ isoform. A significant expression of PADI4, citrullinated peptides and Akt phosphorylation was found during the course of granulocyte-lineage differentiation of HL-60 by ATRA According to the results obtained in the current 2 years, an association between CaMKII and FLS apoptosis is demonstrated. Considering a possible cross-talk between CaMKII and Akt, another cross-talk among CaMKII, Akt and the peptide citrullination process appears to be present. These mechanisms are thought to be important research issue of RA that strengthens a role of CaMKII for a target molecule in RA.

类风湿性关节炎（RA）的发病机制是细胞增殖和凋亡的双重抵抗。其中，我们关注PI 3 K/Akt通路的重要性，在最近的2年里，我们试图研究CaMK II通路的作用。培养的FLS表达CaMK Ⅱ γ和δ，尤其是δ亚型。CaMK Ⅱ化学抑制剂KN 93的加入显著增加了FLS对TRAIL和抗Fas抗体的凋亡敏感性。另外的实验表明，CaMK II诱导的凋亡敏感性现象是通过Akt介导的。CaMKII是一种由Ca离子流入激活的酶。Ca离子内流还激活PADI，PADI是肽瓜氨酸的转录后机制的必需酶。瓜氨酸肽的转录后机制被认为是RA患者产生抗CCP抗体（RA特异性自身抗体）的关键。然而，我们不能检测到瓜氨酸肽培养FLS响应钙离子流入，促炎cytoltines或促凋亡刺激。因此，我们使用人细胞系HL-60进行了实验。HL-60表达CaMK Ⅱ γ亚型。在ATRA诱导HL-60细胞向粒系分化的过程中，PADI 4、瓜氨酸化肽和Akt磷酸化均显著表达。根据近2年的研究结果，CaMK Ⅱ与FLS细胞凋亡有一定的相关性。考虑到CaMKII和Akt之间可能的串扰，CaMKII、Akt和肽瓜氨酸酶过程之间似乎存在另一种串扰。这些机制被认为是RA的重要研究问题，其加强了CaMKII在RA中作为靶分子的作用。

项目成果

EGF activates PI3K-Akt and NF-kappaB via distinct pathways in salivary epithelial cells in Sjogren's syndrome

EGF 通过干燥综合征唾液上皮细胞中的不同途径激活 PI3K-Akt 和 NF-kappaB

• 发表时间: 2007
• 期刊: Rheumatology international 28(2)
• 作者: Nakamura H;Kawakami A;Eguchi K(2番目;他2名)
• 通讯作者: 他2名)

Mechanisms of autoantibody production and the relationship between antuantibodies and the clinical manifestations in Sjogren's syndrome

干燥综合征自身抗体产生机制及抗体与临床表现的关系

• 发表时间: 2006
• 期刊: Translafional Res 148(6)
• 作者: Nakamura H;Kawakami A;Eguchi K
• 通讯作者: Eguchi K

関節リウマチの早期診断と早期からの骨病変進展予測の試み

类风湿关节炎早期诊断和骨病变进展早期预测的尝试

• 发表时间: 2006
• 期刊: 臨床リウマチ 18(4)
• 作者: 川上 純;江口 勝美(1番目;他7名)
• 通讯作者: 他7名)

関節リウマチに対するinfliximabの長期治療効果と安全性:102週での検討

英夫利昔单抗治疗类风湿关节炎的长期疗效和安全性：102 周研究

• 发表时间: 2007
• 作者: Kawakami A(筆頭著者;他13名);Tamai M;Tamai M;玉井 慎美;岩本 直樹;玉井 慎美;岩本 直樹;中村 英樹;有馬 和彦;玉井 慎美;藤川 敬太;荒牧 俊幸;右田 清志;荒牧 俊幸;藤川 敬太;玉井 慎美;岩永 希;折口 智樹;岩永 希
• 通讯作者: 岩永 希

Prognostic Evaluation of Undifferentiated Arthritis (UA) at Baseline Through Magnetic Resonance Imaging (MRI)-Detection of Early Join Damages and Serologic Variables:Results from the Prospective Clinical Study

通过磁共振成像 (MRI) 检测早期关节损伤和血清学变量对基线未分化关节炎 (UA) 进行预后评估：前瞻性临床研究的结果

• 发表时间: 2007
• 作者: Tamai M;Kawakami A;et. al.
• 通讯作者: et. al.