权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Basic approaches for the development of immunomodulatory and anti-inflammatory drugs acting on the signaling molecules

开发作用于信号分子的免疫调节和抗炎药物的基本方法

基本信息

批准号：
16390024
负责人：
KASAHARA Tadashi
金额：
$ 6.66万
依托单位：
Kyoritsu University of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390024/
关键词：
TNF signaling TRAF6 NF-kB Focal adhesion kinase DNA microarray MALDI-TOF MS Apoptosis FAK FAK過剰発現

项目摘要

Many signaling molecules have been identified which act on the IL-1 and TNFa-mediated signaling. We have studied the role of the focal adhesion kinase (FAK) and TNF receptor-associated factors (TRAF) in the cytokine signaling and apoptosis induced by various apoptosis inducing agents. This system was adopted to develop several assay systems to find new immunomodulatory and anti-inflammatory drugs. Our findings are followings.1) We found that FAK deficient MEF derived from FAK-/-mice is more susceptible to the TNFa and actinomycin D-induced apoptosis than the FAK+/-cells, indicating the anti-apoptotic role against the cell-death inducing reagents. In this study, FAK was associated with RIP, while RIP was recruited in the DISC in the FAK-/-cells (Takahashi et al. 2007).2) In addition, TRAF6-/-MEF is more sensitive to the TNFa and actinomycin-D induced cell death. In this system, reactive oxygen species (ROS) was involved in the cell-death and therefore, antioxidant reagent, BHA restored … More ROS-induced cell death. Thus, TRAF6 was involved in the ROS induced apoptosis (Ichikawa et al. 2006).Above two cell-culture systems are found to be easily applicable to the screening antioxidant reagents which protects from apoptosis-inducing conditions.3) We found that FAK-overexpressed HL-60 is resistant against apoptosis induced by the various apoptosis-inducing agents including TRAIL. In contrast, FAK-overexpressed HL-60 is reftractory to the ATRA-induced differentiation. This refactoctory condition was resulted from the hyperphosphorylation of Rb protein and subsequent the c/EBPa inactivation (Hashimoto et al. 2006).4) Glycyrrhizin (GL) and related compounds were found to regulate production of anti-inflammatory chemokines, IL-8 and eotaxin-1 in the human lung fibroblasts. In particularly, 11-deoxo-GL and Hetero-30-OH-GL were effective to inhibit IL-8 and eotaxin-1 (Matsui et al. 2004, 2006). These derivatives are now designed to be studied in in vivo assay.5) Various proteasome inhibitors were found to act differentially in the induction of eotaxin-1 and eotaxin-3 by the TNF and IL-4 in the human lung fibroblast (Rokudai et al. 2006).These study was applicable to the screening of the immunomodulatory and anti-inflammatory agents acting on the various signaling molecules. Less

已经鉴定了许多作用于IL-1和TNF α介导的信号传导的信号传导分子。我们研究了黏着斑激酶（FAK）和肿瘤坏死因子受体相关因子（TRAF）在细胞因子信号转导和各种凋亡诱导剂诱导的细胞凋亡中的作用。该系统被用于开发多种检测系统，以寻找新的免疫调节和抗炎药物。我们的研究结果如下：1）我们发现FAK-/-小鼠来源的FAK缺陷MEF比FAK+/-细胞更容易受到TNF α和放线菌素D诱导的凋亡，表明对细胞死亡诱导剂的抗凋亡作用。在该研究中，FAK与RIP相关，而RIP在FAK-/-细胞中的DISC中募集（Takahashi等，2007）。2）此外，TRAF 6-/-MEF对TNF α和放线菌素-D诱导的细胞死亡更敏感。在该系统中，活性氧参与了细胞死亡，因此，抗氧化剂BHA恢复 ...更多信息 ROS诱导的细胞死亡。因此，TRAF 6参与了ROS诱导的细胞凋亡（Ichikawa et al. 2006）。以上两种细胞培养系统很容易应用于筛选抗氧化剂，以保护细胞免受凋亡诱导条件的影响。3）我们发现过表达FAK的HL-60对包括TRAIL在内的各种凋亡诱导剂诱导的细胞凋亡具有抗性。与此相反，FAK过表达的HL-60细胞对ATRA诱导的分化反应迟钝。这种难治性条件是由Rb蛋白的过度磷酸化和随后的c/EBPa失活引起的（Hashimoto et al.2006）。4）发现甘草甜素（GL）和相关化合物调节人肺成纤维细胞中抗炎趋化因子、IL-8和嗜酸细胞活化趋化因子-1的产生。特别是，11-脱氧-GL和肝素-30-OH-GL可有效抑制IL-8和嗜酸性粒细胞趋化因子-1（Matsui et al. 2004，2006）。这些衍生物现在被设计用于在体内分析中进行研究。5）发现各种蛋白酶体抑制剂在人肺成纤维细胞中通过TNF和IL-4诱导嗜酸细胞活化趋化因子-1和嗜酸细胞活化趋化因子-3方面具有差异性作用（Rokudai et al. 2006）。这些研究适用于筛选作用于各种信号分子的免疫调节剂和抗炎剂。少

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line.

DOI：
10.1016/j.intimp.2004.07.023
发表时间：
2004-12-15
期刊：
International immunopharmacology
影响因子：
5.6
作者：
Matsui S;Matsumoto H;Sonoda Y;Ando K;Aizu-Yokota E;Sato T;Kasahara T
通讯作者：
Kasahara T

Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-□ and IL-4 stimulated Human Lung Fibroblast

TNF-□和IL-4刺激的人肺成纤维细胞对Eotaxin-1/CCL11和Eotaxin-3/CCL26产生的差异调节

DOI：
发表时间：
2006
期刊：
Biol Pharm Bull 29(6)
影响因子：
0
作者：
Rokudai R;Terui Y;Kuniyoshi R;Mishima Y;Mishima Y;Aizu-Yokota E;Sonoda Y;Kasahara T;Hatake K
通讯作者：
Hatake K

Indirubin, a Chinese antileukemia drug, enhances the neutrophilic differentiation of human promyelocyte HL-60 cells.

靛玉红是一种中国抗白血病药物，可增强人早幼粒细胞 HL-60 细胞的中性粒细胞分化。