Analyses of prostaglandin E synthases that represent a potential target for novel anti-inflammatory drugs

对代表新型抗炎药物潜在靶标的前列腺素 E 合酶的分析

基本信息

批准号：
15390031
负责人：
MURAKAMI Makoto
金额：
$ 9.79万
依托单位：
Tokyo Metropolitan Organization for Medical Research (2005)Showa University (2003-2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

This study aims to clarify the functional aspects of three PGE_2 synthases (mPGES-1, mPGES-2 and cPGES) both in vitro and in vivo. In cell culture studies, mPGES-1, a stimulus-inducible, perinuclear enzyme, shows preferential functional coupling with the inducible cyclooxygenase (COX) isozyme, COX-2, to produce PGE_2. mPGES-2, a constitutive enzyme that is initially expressed as a Golgi membrane-associated protein and then released into the cytoplasm after proteolytic removal of the N-terminal hydrophobic domain, is coupled with both constitutive COX-1 and inducible COX-2. cPGES is a cytosolic, constitutive enzyme, and its association with Hsp90 and concomitant phsophorylation by casein kinase-2, an Hsp90 client protein, following Ca^<2+>-evoked stimuli eventually leads to a temporal COX-1-dependent PGE_2 generation. Whereas mPGES-1-deficient mice are normally born, grow and are fertile under normal housing condition, they exhibit reduced nociceptive response, inflammatory granulation … More and arthritis, and tumor growth and metastasis relative to replicate wild-type mice, implying the role of mPGES-1-derived PGE_2 in pain, inflammation and cancer. In contrast, there is an exacerbation of inflammatory bowel disease in mPGES-1-null mice compared with that in wild-type littermates, suggesting an additional contribution of mPGES-1 to the production of the gastrointestinal tissue-protective PGE_2. Thus, even though putative chemicals that specifically inhibit mPGES-1 might be useful as anti-nociceptive, inflammatory, and cancer drugs, some adverse side-effects such as gastrointestinal ulcer should be taken into consideration. Mice deficient in cPGES are perinatal lethal. Some developmental defects are found in several tissues of cPGES-null mice such as skin and lung, in which PGE_2 levels are markedly decreased. In contrast, PGE_2 levels in tissues seemingly unaffected by cPGES knockout, such as heart and liver, are similar between cPGES-null and wild-type mice. However, no such abnormalities have been reported for mice deficient in upstream PGE_2-biosynthetic enzymes or PGE_2 receptors, suggesting that the severe phenotypes occurred in cPGES-deficient mice might result from the lack of some unique function(s), rather than the PGE_2-synthetic function, of cPGES. Less

这项研究旨在阐明体外和体内的功能性驴（MPGES-1，MPGES-2和CPGES）。可诱导的环氧合酶（COX）同工酶Cox-2产生PGE_2，并在蛋白水解去除N-末端疏水性结构域后将其释放到细胞质中CPGE是一种胞质的酶Hsp90，酪蛋白激酶-2（HSP90客户蛋白）伴随着Ca^<2+> evaken刺激，最终会导致颞Cox-1依赖性PGE_2在正常的房屋条件下。，它们表现出降低的降低反应，炎症颗粒状……更多，关节炎，相对于复制野生型小鼠的肿瘤生长和转移，MPGES-1-NULL小鼠中炎性肠病的恶化加剧了，与野生型小鼠相比类型的同窝材料S，即使是特异性抑制MPGES-1的坚硬推定化学物质也可能是有用的ASATI-NOCICICEPGES-1，因为抗Nocical和癌症药物可能是有用的。诸如皮肤和肺部的无效小鼠，其中PGE_2的水平显着降低，例如，诸如心脏和肝脏D野生型野生型小鼠。受体表明，在缺乏CPGE的情况下发生的型号可能是由于缺乏某些独特的功能而导致的，而不是PGE_2合成功能。