Construction and analysis of model organisms for human liver diseases

人类肝脏疾病模型生物的构建与分析

• 批准号: 20390022
• 负责人: NISHINA Hiroshi
• 金额: $ 12.4万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390022/
• 关键词: ノックアウトマウス; メダカ; 肝形成; 肝再生; 脂肪肝; 肝機能; シグナル伝達; モデル生物

We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in the zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. Positional cloning revealed that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. Furthermore, we have succeeded in isolating ken mutation that models human disease non-alcoholic steatohepatitis (NASH). NASH are serious human diseases in the modern world, so ken mutation may shed a new light on the molecular mechanisms of these diseases and the preventive medicine.

我们之前在medaka进行了筛选，以分离肝脏发育受损的突变体。medaka hio突变体在肝脏结构上表现出一种深刻的（但短暂的）缺陷，类似于斑马鱼prometheus （prt）突变体的肝脏形成缺陷，后者的突变发生在wnt2bb基因上。定位克隆表明，hio突变影响编码视黄醛脱氢酶2型（raldh2）的raldh2基因，该酶主要负责维甲酸（RA）的生物合成。我们的数据揭示了意想不到的发现，RA信号正调节medaka肝脏规范所需的wnt2bb基因表达。此外，我们已经成功地分离出模拟人类疾病非酒精性脂肪性肝炎（NASH）的ken突变。NASH是当今世界严重的人类疾病，ken突变可能为研究NASH的分子机制和预防医学提供新的思路。

项目成果

[review] Utility and limitations of SP600125, an inhibitor of stress- responsive c-Jun N-terminal kinase.

[综述] SP600125（一种应激反应性 c-Jun N 末端激酶抑制剂）的实用性和局限性。

• 发表时间: 2010
• 期刊: Curr.Enzym.Inhib. 6
• 作者: Shuhei Tanemura;Tokiwa Yamasaki;Toshiaki Katada;Hiroshi Nishina
• 通讯作者: Hiroshi Nishina

Liver biology and disease: lessons from mutant fish

肝脏生物学和疾病：突变鱼的教训

• 发表时间: 2010
• 作者: 浅岡洋一;仁科博史
• 通讯作者: 仁科博史

共培養系を用いた高効率な異常型プリオンタンパク質伝播実験系の確立

利用共培养系统建立高效繁殖异常朊病毒蛋白的实验系统

• 发表时间: 2009
• 作者: 田中正彦;前濱朝彦;仁科博史
• 通讯作者: 仁科博史

[review] Diverse Physiological Functions of MKK4 and MKK7 during Early Embryogenesis.

[综述] MKK4和MKK7在早期胚胎发生过程中的多种生理功能。

• 发表时间: 2010
• 期刊: J.Biochem. 148
• 作者: Yoichi Asaoka;Hiroshi Nishina
• 通讯作者: Hiroshi Nishina

Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma

• DOI: 10.1038/labinvest.2010.121
• 发表时间: 2010-09-01
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Mashima, Ryuichi;Honda, Kazuho;Yamanashi, Yuji
• 通讯作者: Yamanashi, Yuji