Generation of mice in which the mouse hepatocytes are replaced with the human hepaocytes and its application

2009 Fiscal Year Final Research Report

• Project/Area Number: 19390347
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: MIURA Naoyuki Hamamatsu University School of Medicine, 医学部, 教授 (40165965)
• Co-Investigator(Kenkyū-buntansha): UEZATO Tadayoshi 浜松医科大学, 医学部, 准教授 (40115465) ; SHINMURA Kazuya 浜松医科大学, 医学部, 准教授 (40321880)
• Project Period (FY): 2007 – 2009
• Keywords: ヒト肝細胞 / マウス

Research Abstract

Alb-uPAトランスジェニックマウスに免疫不全scidマウスを交配し、Alb-uPAをトランスジーンにもつ免疫不全マウスを作製した。Alb-uPAホモ免疫不全マウスの生後3週目にヒト肝細胞を脾臓経由で移植すると4週後には、マウスの肝臓の50-100%がヒト肝細胞で置換されたマウスができた(肝臓ヒト化マウス)。肝臓ヒト化マウスに肝化学発癌剤であるジエチルニトロサミンとフェノバルビタールを投与すると、肝細胞腫(アデノーマ)が高頻度で発生した。腫瘍部のRNA解析では、c-Myc,FoxM1,c-Jun,c-Fos,Bmi1,Skp2mRNAが増加していることが判明した。

Research Products

• [Journal Article] A unique expression pattern of Tbx10 in the hindbrain as revealed by Tbx10(lacZ ) allele. (2010)
  • Author(s): Xue, X-D., Kimura W., Wang, B., Hikosaka, K., Itakura, T., Uezato, T., Matsuda, M., Koseki, H., Miura, N.
  • Journal Title: Genesis 48 Pages: 295-302
  • Peer Reviewed
• [Journal Article] Identification of Prox1 targets during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangenesis. (2009)
  • Author(s): Harada, K., Yamazaki, T., Iwata, C., Yoshimatsu, Y., Sase, H., Mishima, K., Morishita, Y., Hirashima, M., Oike, Y., Suda, T., Miura, N., Watabe, T., Miyazone, K.
  • Journal Title: J. Cell Sci 122 Pages: 3923-3930
  • Peer Reviewed
• [Journal Article] Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maruration defects resulting from geene-targeting of the PI3K regulatory isoforms p85a, p55a and p50a. (2009)
  • Author(s): Mouta-Bellum, C., Kirov, A., Micelli-Libby, L., Mancini, M.L., Petrova, T.V., Liaw, L., Prudovsky, I., Thorpe P.E., Miura, N., Cantley L.C., Alitaro, K., Fruman, D.A., Vary, C.P.H.
  • Journal Title: Dev. Dyn 238 Pages: 2690-2699
  • Peer Reviewed
• [Journal Article] Fecal COX-2 plus MMP-7 mRNAassays as a marker for colorectalcancer screening. (2009)
  • Author(s): Takai, T., Kanaoka, S., Yoshida, K., Hamaya, Y., Ikuma, M., Miura, N., Sugimura, H., Kajimura, M., Hishida, A.
  • Journal Title: Can. Epidemiol. Biomarkers Prev 18 Pages: 1888-1893
  • Peer Reviewed
• [Journal Article] Integrin-a9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. (2009)
  • Author(s): Bazigou, E., Xie, S., Chan, C., Weston, A., Miura, N., Sorokin, L., Adams, R., Muro, A.F., Sheppard, D., Makinen, T.
  • Journal Title: Dev. Cell 17 Pages: 175-186
  • Peer Reviewed
• [Journal Article] FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. (2009)
  • Author(s): Norrmen, C., Cheng, J., Miura, N. Puolakkainen, P., Yla-Herttuala, S., Alitaro, K., Petrove, T.V.
  • Journal Title: J. Cell Biol 185 Pages: 439-457
  • Peer Reviewed
• [Journal Article] Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate. (2008)
  • Author(s): Jochumsen, U., Werner, R., Miura, N., Richter-Unruh, A., Hiort, O., Holterhus, P-M.
  • Journal Title: Sex. Dev 2 Pages: 302-308
  • Peer Reviewed
• [Journal Article] The medaka FoxP2, a homologue of human language gene FOXP2, has a diverged structure and function. (2008)
  • Author(s): Itakura, T., Chandra, A., Yang, Z., Xue, X-D., Wang, B., Kimura, W., Hikosaka, K., Inohaya, K., Kudo, A., Uezato, T., Miura, N.
  • Journal Title: J. Biochem 143 Pages: 407-416
  • Peer Reviewed
• [Journal Article] The mouse forkhead gene Foxp2 modulates expression of the lung genes.
  • Author(s): Yang, Z., Hikosaka, K., Sharkar M.T.K., Tamakoshi, T., Chandra, A., wang, B., Itakura T., Xue, X-D., Uezato, T., Kimura W., Miura, N.
  • Journal Title: Life Sciences (in press)
  • Peer Reviewed
• [Journal Article] Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc.
  • Author(s): Mani, S.A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., Kutok, J.L., Hartwell, K.H., Richardson, A.L., Weinberg, R.A.
  • Journal Title: Natl. Acad. Sci. USA 104 Pages: 10069-10074
  • Peer Reviewed
• [Presentation] 心臓形成におけるIrx遺伝子の発現と役割 (2009)
  • Author(s): 三浦直行, 待井将志, ニシャットサルタナ, モハマドシャーカー, 木村航
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜(ワークショップ)
  • Year and Date: 20091200
• [Presentation] マウスフォークヘッド遺伝子Foxp2は肺分化遺伝子の発現を制御する (2009)
  • Author(s): 楊志, 彦坂圭介, 木村航, 上里忠良, 三浦直行
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 20091000
• [Presentation] マウスフォークヘッド遺伝子Foxp2は肺分化遺伝子の発現を制御する (2009)
  • Author(s): 楊志, 彦坂圭介, 木村航, 上里忠良, 三浦直行
  • Organizer: 第61回日本細胞生物学会
  • Place of Presentation: 名古屋
  • Year and Date: 20090600
• [Presentation] 変異Rb蛋白を肝細胞に発現させると肝臓腫瘍を効率におこす (2008)
  • Author(s): 王博, 福本和彦, 彦坂圭介, 三浦直行
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20081200
• [Presentation] The Tbx10 gene is expressed in the superior sulvatory nucleus in the medulla oblongata (2008)
  • Author(s): 薛暁東, 木村航, 板倉達郎, 彦坂圭介, 三浦直行
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20081200
• [Presentation] The medaka FoxP2, a homologue of human language gene FOXP2, has a diverged structure and function. (2008)
  • Author(s): 板倉達郎, 楊志, 薛暁東, 木村航, 彦坂圭介, 三浦直行
  • Organizer: 第60回日本細胞生物学会
  • Place of Presentation: 横浜
  • Year and Date: 20080600
• [Presentation] Tbx10遺伝子は上部唾液分泌神経の有用なマーカーである (2008)
  • Author(s): 薛暁東, 彦坂圭介, 木村航, 三浦直行
  • Organizer: 第41回日本発生生物学会
  • Place of Presentation: 徳島(ワークショップ)
  • Year and Date: 20080500
• [Presentation] メダカFoxP2タンパクの発現と機能について (2007)
  • Author(s): 板倉達郎, Abhishek Chandra, 楊志, 三浦直行
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20071200
• [Presentation] Characterization of the N-terminal signal sequence of Neurogenesin-1 and its role in early bone development (2007)
  • Author(s): Abhisheck Chandra, 板倉達郎, 三浦直行
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20071200
• [Presentation] フォークヘッド遺伝子Foxp2の肺と消化管における発現と機能について (2007)
  • Author(s): 楊志, Abhisheck Chandra, 板倉達郎, 三浦直行
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20071200
• [Presentation] フォークヘッド遺伝子Foxj1の欠損により心臓大血管の左右は腹部臓器の左右とは独立に決定される (2007)
  • Author(s): 三浦直行
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会
  • Place of Presentation: 横浜(ワークショップ)
  • Year and Date: 20071200
• [Presentation] Double axis formation in Xenopus laevis embryos by early perturbation just after insemination. (2007)
  • Author(s): 佐藤英二, 柴田清, 藤江三千男, 呉一心, 上里忠良, 三浦直行
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20071200
• [Presentation] Roles of the Foxj1 and Inv genes in the left-right determination of internal organs in mice (2007)
  • Author(s): Tomoki Tamakoshi, Tatsuo Itakura, Abhisheck Chandra, Tatsuhiko Yokoyama, Naoyuki Miura
  • Organizer: 第40回日本発生生物学会・第59回日本細胞生物学会
  • Place of Presentation: 福岡
  • Year and Date: 20070500
• [Presentation] The Foxf2 gene controls murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. (2007)
  • Author(s): Tao Wang, Tomoki Tamakoshi, Peter Carlsson, Naoyuki Miura
  • Organizer: 第40回日本発生生物学会・第59回日本細胞生物学会
  • Place of Presentation: 福岡
  • Year and Date: 20070500
• [Presentation] フォークヘッド遺伝子Foxf2の腸管における上皮-間葉相互作用について (2006)
  • Author(s): 王滔, 玉越智樹, 薛暁東, 三浦直行
  • Organizer: 日本分子生物学会フォーラム「分子生物学の未来」
  • Place of Presentation: 名古屋
  • Year and Date: 20061200
• [Book] Chapter 88 Introduction to Forkhead (Fox) Genes, in "Inborn Errors of Development: Molecular basis of clinical disorders of morphogenesis" 2nd edition, (Eds. Epstein, CJ, Erickson, RP, Wynshaw-Boris A) (2008)
  • Author(s): Miura, N., Xue, X-D., Itakura, T.
  • Total Pages: 826-833
  • Publisher: Oxford University Press
• [Remarks]
  • URL: http://www2.hama-med.ac.jp/w1a/bio2/index-j.html