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Establishment of screening system to develop therapeutic compound for allergic disease

建立筛选系统以开发过敏性疾病治疗化合物

基本信息

批准号：
13557044
负责人：
KUBO Masato
金额：
$ 10.18万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557044/
关键词：
Cytokine signaling Effector T cell developmer IL-4 Th1 Th2 STAT6 SOCS

项目摘要

After the advanced economic growth, allergic disease, such as pollinosis, asthma and Atopic dermatitis, seriously become social problem in urban area of Japan.Although a steroid and immunosuppressant agent are so far commonly used for the therapeutic treatment of allergic patients, these treatment carried on the harmful side effect in some case, thus the development of novel therapeutic strategy to function more than the side effect would be necessary in the future.The serum of allergic patient contains large quantities of an immunoglobulin E antibody(IgB)reacting with allergen.IgE is secreted from plasma B cells after the class switch of the immunoglobulin gene, and Th2 derived cytokine, IL-4 regulates this class switch process.IL-4 controls the differentiation of Th2 and the IgB class switching in B cells by the signal pathway through its receptor.Therefore, JL-4 receptor mediated signaling pathway would be useful therapeutic target for allergic disease.We established the two hybrid … More system that monitor the interaction either between tyrosine-phosphorylated STAT6 and IL-4 receptor or homodimer of tyrosine-Phosphorylated STAT6, and using this system, we screen the compound to interfere these interaction.We confirmed the inhibitory effect of these compounds as an effect on the class switch of IgB and the activation of STAT6 mediated CD23 promoter activity.As a result of these extensive screening of 10000 compound, 2 compounds are found as candidates.The suppressors of the cytokine signaling(SOCS)protein are due to their action as a negative regulator of the cytokine signal, implicated in the determination of direction for Th1 and Th2 differentiation.We recently found that SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes.Since SOCS3 inhibits IL-12 mediated signaling through the binding with IL-12 receptor beta 2, we generate the screening system to monitor the interaction between SOCS3 and cytoplasmic region of IL-12 receptor beta 2.However, accuracy and sensitivity remain to be unresolved problem. Less

在经济高速增长后，花粉症、哮喘和特应性皮炎等变态反应性疾病在日本城市严重成为社会问题。虽然迄今为止，类固醇和免疫抑制剂一直被用于治疗过敏患者，但这些治疗方法在某些情况下存在有害的副作用，因此未来需要开发新的治疗策略，以发挥更多的作用而不是副作用。过敏患者的血清中含有大量与过敏原反应的免疫球蛋白E抗体(IGB)。免疫球蛋白基因和Th2衍生细胞因子的类别转换后，血浆B细胞分泌IgE。IL-4通过其受体介导的信号通路控制B细胞Th2型细胞的分化和IgB类细胞的转换。因此，JL-4受体介导的信号通路将成为治疗变态反应性疾病的有效靶点。我们建立了两种杂交…更多的监测酪氨酸磷酸化的STAT6与IL-4受体或酪氨酸磷酸化的STAT6的同源二聚体之间的相互作用的系统，我们利用这个系统筛选出干扰这些相互作用的化合物。我们证实了这些化合物对免疫球蛋白的类转换和STAT6介导的CD23启动子活性的抑制作用。通过对10000个化合物的广泛筛选，发现2个化合物被认为是候选化合物。细胞因子信号转导(SoCs)蛋白的抑制是由于它们作为细胞因子信号的负调节因子，最近我们发现SOCS3和SOCS5分别主要在Th2和Th1细胞中表达，并相互抑制Th1和Th2的分化过程。由于SOCS3通过与IL-12受体β2结合来抑制IL-12介导的信号转导，所以我们建立了筛查系统来监测SOCS3与IL-12受体β2细胞质区域的相互作用，但准确性和敏感性仍有待解决。较少