The functional gene regulation in pathological keratinization

病理性角化中的功能基因调控

基本信息

批准号：
11670845
负责人：
YAMANISHI Kiyofumi
金额：
$ 2.3万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Transglutaminase 1 (TGase 1) is a keratinization specific enzyme which catalyzes epsilon-(gamma-glutamyl) lysine cross-linking of substrate proteins to generate the cornified envelope at the cell periphery of the stratum corneum. We examined conjunctiva covering cornea in five eyes in the chronic cicatricial phase of Stevens-Johnson syndrome. In situ hybridization revealed transglutaminase 1 (keratinocyte transglutaminase) mRNA in suprabasal cells of the abnormally thickened corjunctival epithelium in all Stevens-Johnson syndrome patients. In contrast, no message was detected in normal conjunctival or corneal epithelia. We speculate that in Stevens-Johnson syndrome, epithelial hyperproliferation, and transglutaminase 1 gene expression lead to the pathological keratinization of ocular surface mucosal epithelia.We have shown that disruption of the TGase 1 gene in mice results in neonatal lethality, absence of the cornified envelope, and impaired skin barrier function. Based on the importance of TGase 1 in epidermal morphogenesis, we have now assessed its role in wound healing. In neonatal mouse skin, TGase 1 mRNA as well as keratin 6alpha was induced in the epidermis at the wound edges as early as 2 hours after injury and that expression continued in the migrating enidermis until completion of re-epithelialization. The TGase 1 enzyme co-localized on the plasma membrane of migrating keratinocytes with involucrin, but not with loricrin, which suggests the premature assembly of the cornified envelope. Similar injuries to TGase 1 knockout mouse skins grafted on athymic nude mice showed substantial delays in wound healing concomitant with sustained K6alpha mRNA induction. From these results, we suggest that activation of the TGase 1gene is essential for facilitated repair of skin injury.

转谷氨酰胺酶1（TGASE 1）是一种角质化特异性酶，催化底物蛋白的Epsilon-（γ-谷氨酰基）赖氨酸交联，以产生层状层的细胞外围的玉米夹。我们检查了史蒂文斯 - 约翰逊综合症的慢性尾cacatricial阶段中覆盖角膜的结膜。原位杂交揭示了所有史蒂文斯 - 约翰逊综合症患者的异常增厚的结核上皮上皮细胞上prabasal细胞中的转谷氨酰胺酶1（角质形成细胞转谷氨酰胺酶）mRNA。相比之下，在正常的结膜或角膜上皮中未检测到任何信息。 We speculate that in Stevens-Johnson syndrome, epithelial hyperproliferation, and transglutaminase 1 gene expression lead to the pathological keratinization of ocular surface mucosal epithelia.We have shown that disruption of the TGase 1 gene in mice results in neonatal lethality, absence of the cornified envelope, and impaired skin barrier function.基于TGASE 1在表皮形态发生中的重要性，我们现在评估了其在伤口愈合中的作用。在新生小鼠皮肤中，TGASE 1 mRNA以及角蛋白6阿尔法在伤口边缘的表皮中诱导，最早在受伤后2小时，并且在迁移的enidermis中持续这种表达，直到完成上皮化。 TGASE 1酶在迁移角质形成细胞的质膜上共定位于含有依赖蛋白，但与Loricrin互相迁移，这表明质子的包膜过早组装。与TGASE 1敲除小鼠的敲除小鼠皮肤相似的损伤表现出与持续的K6alpha mRNA诱导的伤口愈合相关的延迟。从这些结果中，我们建议Tgase 1Gene的激活对于促进皮肤损伤的修复至关重要。