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Development of the preventive fetal medication of which a therapeutic target is improvement of the severity of cleft palate phenotype in the cleft palate model mouse

开发以改善腭裂模型小鼠腭裂表型严重程度为治疗目标的预防性胎儿药物

基本信息

批准号：
21592349
负责人：
TAKIGAWA Toshiya
金额：
$ 2.91万
依托单位：
Asahi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

It is well known that cleft palate phenotype in humans is varied and widely accepted that the cause of human cleft palate is accountable by"multi-factorial theory". However, almost all the cleft palate phenotype in the cleft palate models using laboratory animals showed complete cleft palate only, so that what kind of factors that produce the phenotypic polymorphism of human cleft palate remains enigmatic and the mechanism underlying phenotypic polymorphism of human cleft palate wait for clarification. This study aimed to demonstrate that the epigenetic modifier produces a variety of cleft palate phenotype by using Tgf-beta 3 knockout C57BL6/J mice, whose homozygous fetuses show complete cleft palate only. Furthermore, this study challenged development of the preventive fetal medication using a DNA methyl transferase inhibitor RG108, of which therapeutic target is improvement of the severity of cleft palate phenotype. By using a newly developed in vitro analytic system, I found that al … More though palatal medial edge epithelial(MEE) cells of Tgf-beta 3-null C57BL6/J mouse fetuses have no ability to bring about epithelial-mesenchymal transformation(EMT) and palate fusion, they can undergo spatially specific EMT and partially fuse to the opposed palate by in vitro medication of a DNA methyltransferase inhibitor RG108.In addition, it was found that when the Tgf-beta 3-null mouse fetuses exposed to RG108 in utero, some of them showed variedly incomplete cleft palates, which is remarkably similar to the cleft palate phenotypes observed in humans. In this experimental model, DNA CG islands in the Igf2r sense promoter region became highly demethylated more than those in the intronic Igf2r antisense promoter region, which esulted in the strong expression of IGF2R in both of the epitheium and mesenchyme of the palatal tissues more than those in controls.Taken those results together, this study provided a new insight into the epigenetic mechanism underlying the cause of phenotypic variation of cleft palate phenotype and suggested, for the first time, the possibility of the preventive fetal medication of which a therapeutic target is improvement of the severity of cleft palate phenotype. Less

众所周知，人类腭裂的表型是多样的，人们普遍认为人类腭裂的病因是由“多因素理论”解释的。然而，使用实验动物建立的腭裂模型中，几乎所有的腭裂表型都只表现为完全性腭裂，因此什么样的因素产生人类腭裂表型多态性仍然是个谜，人类腭裂表型多态性的机制有待澄清。本研究旨在通过使用Tgf-β 3基因敲除的C57 BL 6/J小鼠证明表观遗传修饰物产生多种腭裂表型，其纯合子胎儿仅显示完全腭裂。此外，该研究挑战了使用DNA甲基转移酶抑制剂RG 108的预防性胎儿药物的开发，其治疗目标是改善腭裂表型的严重程度。通过使用新开发的体外分析系统，我发现， ...更多信息尽管TGF-β 3缺失的C57 BL 6/J小鼠胎儿的腭中缘上皮（MEDIAL EDGE PETROLET）细胞没有引起上皮-间充质转化（EMT）和腭融合的能力，但它们可以通过DNA甲基转移酶抑制剂RG 108的体外药物治疗进行空间特异性EMT并部分融合到相对的腭。此外，发现当TGF-β 3缺失的小鼠胎儿在子宫内暴露于RG 108时，它们中的一些显示出各种不完全的腭裂，这与在人类中观察到的腭裂表型非常相似。在本实验模型中，IGf 2 r正义启动子区的DNA CG岛比内含子的IGf 2 r反义启动子区的DNA CG岛更高程度地去甲基化，这导致IGF 2 R在腭上皮和间充质中的强表达高于对照组。这项研究为腭裂表型变异的表观遗传机制提供了新的见解，并首次提出，以改善腭裂表型严重程度为治疗目标的预防性胎儿用药的可能性。少