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Establishment of simulation model for human drug metabolism by bioartificial liver

生物人工肝人体药物代谢模拟模型的建立

基本信息

批准号：
16590441
负责人：
NAGAO Takeshi
金额：
$ 2.24万
依托单位：
Tokyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

项目摘要

We have continued to study by using radial flow bio artificial liver. The expression of CYP3A4 was extremely increased after culturing liver cells in this system. We used FLC cells which originally expressed CYP3A4 and keep high function. After we cultured other liver cells that express CYP3A4 in RFB, CYP3A4 mRNA expressed much more than monolayer culture as well as FLC cells. Furthermore, we cultured GS3A4-HepG2 which introdued gene of glutamin synthetase and CYP3A4 in RFB. As a result, we determined that annmonium was metabolized effectively by those cells under RFB culture.Next, we investigated whether other several liver cell lines are suitable for RFB culture or not. We got the results that the cells which those doubling time were shorter than 24hr could culture on RFB. We speculated that the cells which doubling time was longer than 24hr might be thrown away before attaching on culture matrix. We presented these results at the Japanese congress of regeneration on 2005.On the othe … More r hand, we investigated the differences of expression of CYP1A1, 2D6, 2A6, 2C9, and 2C19 except for CYP3A4 after culturing on RFB or monolayer. As a result, we only got the differences of expression of 2D6 after culturing between them. We could not get the differences of 1A1, which means that enzyme associated with tumorgenesis did not induce.But, expression of arginosuccinate lyase, carbamoyl-p-synthetase, argininosuccinate synthetase that are uremic enzyme on those cell lines increased after RFB culture, and their production of alphafetoprotein (AFP) was inhibited.Furthermore, we also tried to culture kidney cells on RFB because we want to apply RFB for treatment of hepatocellular syndrome.Among them, proximal tubular cells (PTC) were capable of culture on RFB and their function also was increased. For example, expression of CYP27 was increased and expression extracellular matrix was increased on high glucose/hypoxic culture of PTC by using RFB. These results indicated that both high glucose and hypoxia might be necessary to induce acute renal failure. We presented these results at the congress of regeneration on 2005 and congress of Tokyo medical university on 2006, and Dr.Jojima got the grant from Tokyo medical university. Finally, we reported these results on Journal of Tokyo medical university on 2006. Less

我们继续应用径向流生物人工肝进行研究。在此系统中培养肝细胞后，CYP3A4的表达显著增加。我们使用的FLC细胞最初表达CYP3A4，并保持高功能。在RFB中培养其他表达CYP3A4的肝细胞后，CYP3A4 mRNA的表达明显高于单层培养和FLC细胞。在此基础上，我们在RFB中培养了转谷氨酰胺合成酶基因和CYP3A4基因的GS 3A4-HepG2。因此，我们确定在RFB培养下，这些细胞有效地代谢铵。接下来，我们研究了其他几种肝细胞系是否适合RFB培养。结果表明，倍增时间小于24小时的细胞可以在RFB上培养。我们推测倍增时间超过24小时的细胞可能在贴壁前就被丢弃了。我们在2005年的日本再生大会上介绍了这些结果。 ...更多信息另一方面，我们研究了在RFB和单层细胞上培养后，CYP1A1、2D6、2A6、2C9和2C19（CYP3A4除外）表达的差异。结果表明，两种细胞在培养后2D6的表达量存在差异。结果表明，在RFB培养后，上述细胞株上的尿毒症酶--琥珀酸裂解酶、氨甲酰基-β-合成酶、氨基琥珀酸合成酶的表达增加，甲胎蛋白（AFP）的产生受到抑制，而1A1的表达没有明显差异，说明与肿瘤发生相关的酶没有诱导作用。为了将RFB应用于肝细胞综合征的治疗，我们还尝试了在RFB上培养肾细胞，其中近端肾小管细胞（PTC）在RFB上培养，其功能也得到了增强。如高糖低氧培养的PTC细胞，RFB可使细胞色素P450 27的表达增加，细胞外基质的表达增加。提示高糖和缺氧可能是急性肾功能衰竭发生的必要条件。我们在2005年的再生大会和2006年的东京医科大学大会上介绍了这些结果，城岛博士获得了东京医科大学的资助。最后，我们在2006年东京医科大学学报上报道了这些结果。少

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ラジアルフロー型バイオリアクターを用いた糖尿病性腎障害病態の解析

使用径向流生物反应器分析糖尿病肾损伤病理学

DOI：
发表时间：
2006
期刊：
東京医科大学雑誌 64(5)
影响因子：
0
作者：
Munehide M;et al.;Yamaori S et al.;Lei Huang et al.;城島嘉麿
通讯作者：
城島嘉麿

In vitro analytic model of diabetes mellitus glomerulonephropathy using a bioartificial column

使用生物人工柱的糖尿病肾小球肾病的体外分析模型

DOI：
发表时间：
2006
期刊：
Journal of Tokyo medical university vol64(5)
影响因子：
0
作者：
Munehide M;et al.;Yamaori S et al.;Lei Huang et al.;城島嘉麿;Ueda S.;Saruwatari J et al.;Yoshihiro Hotta et al.;Y.Jojima
通讯作者：
Y.Jojima