Development of new strategy focusing on transcription factor as the therapeutic target for intractable bone and joint disease

开发以转录因子为治疗难治性骨关节疾病靶点的新策略

基本信息

批准号：
17390417
负责人：
TOMITA Tetsuya
金额：
$ 10.5万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390417/
关键词：
therapy with nucleic acid arthritis osteoarthritis osteosarcoma lung metastasis NFkB E2F transcription factor デコイ型核酸医薬破骨細胞

项目摘要

1. In previous research, we could confirm the suppressive effect of NFkB decoy oligonucleotides for arthritis and joint destruction in rat or monkey animal model. We are preparing our plan for clinical application of NFkB decoy oligonucleotides.2. After the IL-lb stimulation to human primary cultured cartilage, the decrease of expression of aggrecan and type II collagen in cartilage was prevented by adding NFkB decoy oligonucleotides. From this result, the suppressive effect of NFkB decoy oligonucleotides for degeneration and destruction of human cartilage was suggested and it is supposed that NFkB decoy oligonucleotides would have protective effect for human cartilage when injected into the joints of patients suffered from rheumatoid arthritis or osteoarthritis.3. We confirmed the suppressive effect of NFkB decoy oligonucleotides for arthritis in animal model by injection into the joints. We are now studying whether NFkB decoy oligonucleotides have suppressive effect for arthritis in mouse arthritis model by intravenous administration.4. We are studying the property of ribbon-type (circular dumbbell-type) decoy oligonucleotides with the intension to increase the stability of oligonucleotides in vivo. In our previous data, ribbon-type decoy oligonucleotides showed higher resistance to degradation when incubated with nuclease or joint fluid. Ribbon-type decoy oligonucleotides are supposed to have higher resistance against nuclease and have higher stability.5. Intranasal administration of NFkB decoy oligonucleotides decreased the number of lung metastasis and prolonged survival period in murine lung metastatic model implanted with murine osteosarcoma cell line (LM8) which has high metastatic potential to the lung.

1. 在之前的研究中，我们可以在大鼠或猴动物模型中证实NFkB诱饵寡核苷酸对关节炎和关节破坏的抑制作用。我们正在制定NFkB诱饵寡核苷酸的临床应用计划。2．对人原代培养软骨进行IL-1b刺激后，通过添加NFkB诱饵寡核苷酸来防止软骨中聚集蛋白聚糖和II型胶原表达的降低。由此结果表明，NFkB诱饵寡核苷酸对人类软骨的变性和破坏具有抑制作用，并且推测当NFkB诱饵寡核苷酸注射到患有类风湿性关节炎或骨关节炎的患者的关节中时，会对人类软骨具有保护作用。 3 。我们通过关节注射证实了 NFkB 诱饵寡核苷酸对动物模型关节炎的抑制作用。我们正在研究NFkB诱饵寡核苷酸静脉注射对小鼠关节炎模型是否具有抑制关节炎的作用。4．我们正在研究带状（圆形哑铃型）诱饵寡核苷酸的特性，旨在提高寡核苷酸在体内的稳定性。在我们之前的数据中，带状诱饵寡核苷酸在与核酸酶或关节液一起孵育时表现出更高的抗降解性。带状诱饵寡核苷酸应该具有较高的核酸酶抗性和较高的稳定性。 5．在植入具有高肺转移潜力的鼠骨肉瘤细胞系（LM8）的鼠肺转移模型中，鼻内施用NFkB诱饵寡核苷酸可减少肺转移的数量并延长生存期。