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

Development of rational immunosuppressive therapy in organ transplantation based on pharmacogenomic and proteomic research

基于药物基因组学和蛋白质组学研究开发器官移植中合理的免疫抑制治疗

基本信息

批准号：
14370787
负责人：
TANIGAWARA Yusuke
金额：
$ 8.9万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

We found gene markers for predicting acute rejection and therapeutic effect of immunosuppressive agents in rat cardiac and liver transplantation. We also identified protein markers to predict acute rejection in rat small bowel transplantation.Rat cardiac transplantation model :Profiling of DNA expression followed by quantitative real-time PCR analysis revealed that the expression of six candidate genes (IRF1, PSMB9, TAP1, CTSS, NOS2, PIM1) in peripheral blood were significantly induced by acute rejection. The induction was reversed by cyclosporine administration. A relationship between the cyclosporine trough concentration and the gene expression could be well described by a sigmoid Emax model. The results suggested that the expression of these candidate genes were good predictors for rejection episode and therapeutic effect of immunosuppressive agents.Rat liver transplantation model :We found that the expression of four genes in peripheral blood were significantly increased by acute rejection in the DNA microarray analysis followed by quantitative PCR. Immunosuppressive agents reduced the expression of these candidate genes. The results suggested that the expression of these genes in peripheral blood would be a good predictor for acute rejection and therapeutic effect of immunosuppressive drugs.Rat small bowel transplantation model :We identified three possible biomarkers (10.1,13.0,14.8 kDa) in peripheral blood that reflected acute rejection after small bowel transplantation. Among them, lysozyme (14.8 kDa) may be useful for detecting acute rejection and for monitoring the pharmacological effects of immunosuppressants, whereas migration inhibitory factor-related protein (MRP)-8 (10.1 kDa) and MRP-14 (13.0 kDa) may be useful for detecting the early stage of allograft rejection.

我们发现了预测大鼠心脏和肝脏移植急性排斥反应和免疫抑制剂治疗效果的基因标记。大鼠心脏移植模型：实时荧光定量PCR检测结果显示，6个候选基因（IRF 1，PSMB 9，TAP 1，CTSS，NOS 2，PIM 1）在移植后外周血中的表达明显受到急性排斥反应的诱导。环孢霉素可逆转该诱导作用。环孢素谷浓度和基因表达之间的关系可以很好地描述由S形Emax模型。结果提示，这些候选基因的表达可作为预测排斥反应发生和免疫抑制剂治疗效果的良好指标。大鼠肝移植模型：通过DNA微阵列分析和定量PCR检测，发现急性排斥反应后外周血中4个基因的表达显著增加。免疫抑制剂降低了这些候选基因的表达。结果提示，外周血中这些基因的表达可作为预测急性排斥反应和免疫抑制剂治疗效果的良好指标。大鼠小肠移植模型：我们在外周血中鉴定了三种可能反映小肠移植后急性排斥反应的生物标志物（10.1，13.0，14.8kDa）。其中溶菌酶（14.8 kDa）可用于检测急性排斥反应和监测免疫抑制剂的药理作用，而移动抑制因子相关蛋白（MRP）-8（10.1 kDa）和MRP-14（13.0 kDa）可用于检测移植物排斥反应的早期阶段。