A new selection system of suitable immunosuppressive drugs for each pancreatic islet transplantation using epigenetic analysis in a three-dimensional culture system

• Project/Area Number: 24659596
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General surgery
• Research Institution: Meiji University
• Principal Investigator: MASAKI NAGAYA 明治大学, 公私立大学の部局等, 教授 (90329300)
• Co-Investigator(Kenkyū-buntansha): NAGASHIMA Hiroshi 明治大学, 農学部, 教授 (50318664) ; UMEYAMA Kazuhiro 明治大学, 研究・知財戦略機構, 特任准教授 (70342699) ; WATANABE Masato 明治大学, 研究・知財戦略機構, 特任講師 (00321688) ; ARAI Yoshikazu 明治大学, 研究・知財戦略機構, 研究推進員 (90614769)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 糖尿病 / 膵ランゲルハンス島 / 膵島移植 / 免疫抑制剤 / ヒト糖尿病類似モデルブタ / エピゲノム / パーソナライズド

Research Abstract

The problem with pancreatic islet transplantation for type 1 diabetes is that the immunosuppressive drugs used can damage pancreatic beta cells. This project aimed to establish a new selection system of suitable immunosuppressive drugs for each islet transplantation using epigenetic analysis in a three-dimensional culture system. We first isolated islets from a transgenic pig specifically expressing the green fluorescent protein in the beta cells. These islets were cultured in the presence of an immunosuppressive drug. Thereafter, epigenetic analysis of the islets was performed. With time, we observed epigenetic changes in the insulin gene promoter of the islets in a certain group, although there was no change in their configuration. Our system can evaluate the short-term influence of immunosuppressive drugs on pancreatic islets, the system may be used to determine which immunosuppressive drugs are specifically suitable for each human islet transplantation.

Research Products

• [Journal Article] Transgenic pigs with pancreas specific expression of green fluorescent protein (2014)
  • Author(s): Matsunari H, Kobayashi T, Watanabe M, Umeyama K, Nakano K, Kanai T, Mat suda T, Nagaya M, Hara M, Nakauchi H, Nagashima H
  • Journal Title: J Reprod Dev Volume: (Epub ahead of print)
  • NAID: 130003390840
  • Peer Reviewed
• [Journal Article] Transgenic pigs with pancreas specific expression of green fluorescent protein (2014)
  • Author(s): Matsunari H, Kobayashi T., Watanabe M, Umeyama K, Nakano K, Kanai T, Matsuda T, Nagaya M, Hara M, Nakauchi H, Nagashima H
  • Journal Title: J Reprod Dev. Volume: Epub ahead of print
  • NAID: 130003390840
  • Peer Reviewed
• [Journal Article] Production of iabetic offspring using cryopreserved epididymal sperm by in vitro fertilization and intrafallopian insemination techniques in transgenic pigs (2013)
  • Author(s): Umeyama K, Honda K, Matsunari H, Nakano K, Hidaka T, Sekiguchi K, Mochizuki H, Takeuchi Y, Fu j iwara T, Watanabe M, Nagaya M, Nagashima H
  • Journal Title: J Reprod Dev Volume: 59 Pages: 599-603
  • Peer Reviewed
• [Journal Article] Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs (2013)
  • Author(s): Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, Kobayashi T, Yamaguchi T, Sumazaki R, Herzenberg LA, Nakauchi H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 4557-62
  • Peer Reviewed
• [Journal Article] Production of diabetic offspring using cryopreserved epididymal sperm by in vitro fertilization and intrafallopian insemination techniques in transgenic pigs. (2013)
  • Author(s): Umeyama K, Honda K, Matsunari H, Nakano K, Hidaka T, Sekiguchi K, Mochizuki H, Takeuchi Y, Fujiwara T, Watanabe M, Nagaya M, Nagashima H.
  • Journal Title: J Reprod Dev. Volume: 59 Pages: 599-603
  • NAID: 130003361059
  • Peer Reviewed
• [Journal Article] Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. (2013)
  • Author(s): Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, Kobayashi T, Yamaguchi T, Sumazaki R, Herzenberg LA, Nakauchi H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Issue: 12 Pages: 4557-62
  • DOI: 10.1073/pnas.1222902110
  • Peer Reviewed
• [Journal Article] Advancing pig cloning technologies towards application in regenerativemedicine (2012)
  • Author(s): Nagashima H, Matsunari H, Nakano K, Watanabe M, Umeyama K, Nagaya M
  • Journal Title: Reprod Domest Anim Volume: 47 Suppl 4 Pages: 120-6
  • Peer Reviewed
• [Journal Article] Advancing pig cloning technologies towards application in regenerative medicine. (2012)
  • Author(s): Nagashima H, Matsunari H, Nakano K, Watanabe M, Umeyama K, Nagaya M.
  • Journal Title: Domest Anim. Volume: Suppl 4 Issue: s4 Pages: 120-6
  • DOI: 10.1111/j.1439-0531.2012.02065.x
  • Peer Reviewed
• [Presentation] In vivo exogenic organ generation with organogenesis-disabled cloned pigs as a platform (2014)
  • Author(s): Matsunari H, Nakano K, Kanai T, Matsuda T, Maehara M, Watanabe M, Umeyama K, Nagaya M, Nakauchi H, Nagashima H
  • Organizer: 40th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Reno, USA
• [Presentation] 膵臓欠損ブタ胎仔を用いた外来性細胞由来膵臓形成の試み (2014)
  • Author(s): 松成ひとみ、浅野吉則、小林美里奈、内倉鮎子、渡邊將人、梅山一大、長屋昌樹、中内啓光、長嶋比呂志
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 京都
• [Presentation] In vivo exogenic organ generation with organogenesis-disabled cloned pigs as a platform. (2014)
  • Author(s): Matsunari H, Nakano K, Kanai T, Matsuda T, Maehara M, Watanabe M, Umeyama K, Nagaya M, Nakauchi H, Nagashima H
  • Organizer: 40th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Reno, USA.
• [Presentation] 膵臓欠損ブタ胎仔を用いた外来性細胞由来膵臓形成の試み. (2014)
  • Author(s): 松成ひとみ、浅野吉則、小林美里奈、内倉鮎子、渡邊將人、梅山一大、長屋昌樹、中内啓光、長嶋比呂志.
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 京都.
• [Presentation] In vivo generation of exogenic pancreas in apancreatic cloned pigs via blastocyst complementation (2013)
  • Author(s): Matsunari H, Nakano K, Kanai T, Matsuda T, Maehara M, Watanabe M, Umeyama K, Nagaya M, Nakauchi H, Nagashima H
  • Organizer: 12th Congress of International Xenotransplantation Association
  • Place of Presentation: Osaka
• [Presentation] Generation of a double-transgenic pig with pancreas-specific green and liver-specific red fluorescence (2013)
  • Author(s): Matsunari H, Nakano K, Kanai T, Sakai R, Watanabe M, Umeyama K, Kobayashi T, Yamaguchi T, Shiota A, Nagaya M, Nakauchi H, Nagashima H
  • Organizer: 39th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Hannover, Germany
• [Presentation] Production of chimeric porcine fetuses by aggregation method using parthenogenetic embryos (2013)
  • Author(s): Nakano K, Watanabe M, Matsunari H, Matsuda T, Honda K, Maehara M, Kanai T, Hayashida G, Kobayashi M, Umeyama K, Fujishiro S, Mizukami Y Nagaya M, Hanazono Y, Nagashima H
  • Organizer: 39th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Hannover, Germany
• [Presentation] ガラス化保存された体外成熟/体外受精胚を用いた糖尿病モデル遺伝子改変ブタの作出 (2013)
  • Author(s): 松村幸奈,前原美樹,本田香澄,林田豪太,倉本桃子,中野和明,松成ひとみ,小林美里奈,内倉鮎子,浅野吉則,渡邊将人,梅山一大,長屋昌樹,長嶋比呂志
  • Organizer: 第106回日本繁殖生物学会大会
  • Place of Presentation: 東京
• [Presentation] In vivo generation of exogenic pancreas in apancreatic cloned pigs via blastocyst complementation. (2013)
  • Author(s): Matsunari H, Nakano K, Kanai T, Matsuda T, Maehara M, Watanabe M, Umeyama K, Nagaya M, Nakauchi H, Nagashima H.
  • Organizer: 12th Congress of International Xenotransplantation Association (IXA)
  • Place of Presentation: Osaka, Japan.
• [Presentation] ガラス化保存された体外成熟／体外受精胚を用いた糖尿病モデル遺伝子改変ブタの作出. (2013)
  • Author(s): 松村幸奈, 前原美樹, 本田香澄, 林田豪太, 倉本桃子, 中野和明, 松成ひとみ, 小林美里奈, 内倉鮎子, 浅野吉則, 渡邊将人, 梅山一大, 長屋昌樹, 長嶋比呂志
  • Organizer: 第106回日本繁殖生物学会大会:
  • Place of Presentation: 東京.
• [Presentation] Generation of a double-transgenic pig with pancreas-specific green and liver-specific red fluorescence. (2013)
  • Author(s): Matsunari H, Nakano K, Kanai T, Sakai R, Watanabe M, Umeyama K, Kobayashi T, Yamaguchi T, Shiota A, Nagaya M, Nakauchi H, Nagashima H.
  • Organizer: 39th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Hannover, Germany
• [Presentation] Production of chimeric porcine fetuses by aggregation method using parthenogenetic embryos. (2013)
  • Author(s): Nakano K, Watanabe M, Matsunari H, Matsuda T, Honda K, Maehara M, Kanai T, Hayashida G, Kobayashi M, Umeyama K, Fujishiro S, Mizukami Y, Nagaya M, Hanazono Y, Nagashima H.
  • Organizer: 39th Annual Conference of the International Embryo Transfer Society
  • Place of Presentation: Hannover, Germany
• [Presentation] 遺伝子改変ブタ・クローンブタのトランスレーショナルリサーチへの応用 (2012)
  • Author(s): 長嶋比呂志、松成ひとみ、渡邊将人、梅山一大、長屋昌樹
  • Organizer: 日本実験動物医学会
  • Place of Presentation: 大分県
  • Year and Date: 2012-05-23
• [Presentation] In vitro modeling of al-antitrypsin deficiency using induced pluripotent stem cell-derived hepatocytes froma 1-antitrypsin deficient patients (2012)
  • Author(s): Tafaleng EN, Han B, Hale P, Nagaya M, Duncan SA, Sto l s DB, Strom SC, Fox IJ
  • Organizer: The 63rd annual meeting of the American Association for the Study of Liver disease
  • Place of Presentation: Boston, USA
• [Presentation] Transmission and expression of a retrovirally introduced red fluorescent protein gene in successive generations of transgenic pigs (2012)
  • Author(s): Kanai T, Matsunari H, Takeuchi Y, Honda K, Maehara M, Nakano K, Takayanagi S, Watanabe M, Umeyama K, Tada N, Onodera M, Nagaya M, Nakauchi H, Nagashima H
  • Organizer: International Congress on Animal Reproduction
  • Place of Presentation: Vancouver, Canada
• [Presentation] Development of a feasible verification system for pluripotent stem cells using porcine parthenogenetic embryos (2012)
  • Author(s): Nakano K, Watanabe M, Matsunari H, Matsuda T, Honda K, Maehara M, Kanai T, Arai Y, Umeyama K, Fu j i shiro S, Nagaya M, Nagashima H
  • Organizer: 10^<th> International Societ for Stem Cell Research
  • Place of Presentation: Yokohama
• [Presentation] 遠赤色蛍光蛋白monomeric Plumを発現するトランスジェニックブタの作出とその利用 (2012)
  • Author(s): 渡邊將人、松成ひとみ、小林美里奈、中野和明、竹内靖浩、前原美樹、金井貴博、松村幸奈、林田豪太、倉本桃子、坂井理恵子、梅山一大、渡辺信之、小野寺雅史、長屋昌樹、長嶋比呂志
  • Organizer: 第35回日本分子生物学会大会
  • Place of Presentation: 福岡
• [Presentation] ブタ単為発生胚を用いた凝集キメラ作出法 (2012)
  • Author(s): 中野和明、渡邊將人、松成ひとみ、松田泰輔、本田香澄、前原美樹、竹内靖浩、金井貴博、新井良和、梅山一大、藤城修平、長屋昌樹、花園豊、長嶋比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: 筑波
• [Presentation] 膵・肝二色蛍光発現するトランスジェニックブタの開発 (2012)
  • Author(s): 松成ひとみ、金井貴博、坂井理恵子、中野和明、渡邊將人、梅山一大、高柳就子、小林俊寛、山口智之、塩田明、長屋昌樹、中内啓光、長嶋比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: 筑波
• [Presentation] 遠赤色蛍光蛋白monomeric Plumを発現するトランスジェニックブタの作出 (2012)
  • Author(s): 渡邊將人、松成ひとみ、小林美里奈、中野和明、前原美樹、金井貴博、松村幸奈、林田豪太、倉本桃子、坂井理恵子、梅山一大、渡邊信之、小野寺雅史、長屋昌樹、長嶋比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: 筑波
• [Presentation] 再生医療研究のための大型動物モデルの開発 (2012)
  • Author(s): 長嶋比呂志、松成ひとみ、中野和明、渡邊将人、梅山一大、長屋昌樹
  • Organizer: 第12回日本抗加齢医学会総会
  • Place of Presentation: 横浜
• [Presentation] 遠赤色蛍光蛋白monomeric Plumを発現するトランスジェニックブタの作出とその応用 (2012)
  • Author(s): 渡邊將人、松成ひとみ、小林美里奈、中野和明、竹内靖浩、前原美樹、金井貴博、松 村幸奈、林田豪太、倉本桃子、坂井理恵子、梅山一大、渡辺信之、小野寺雅史、長屋 昌樹、長嶋比呂志
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡
• [Presentation] 遠赤色蛍光蛋白monomeric Plumを発現するトランスジェニックブタの作出 (2012)
  • Author(s): 渡邊將人、松成ひとみ、小林美里奈、中野和明、前原美樹、金井貴博、松村幸奈、林 田豪太、倉本桃子、坂井理恵子、梅山一大、渡辺信之、小野寺雅史、長屋昌樹、長嶋 比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: つくば市、筑波大学
• [Presentation] 膵・肝二色蛍光発現するトランスジェニックブタの開発 (2012)
  • Author(s): 松成ひとみ、金井貴博、坂井理恵子、中野和明、渡邊將人、梅山一大、高柳就子、小 林俊寛、山口智之、塩田明、長屋昌樹、中内啓光、長嶋比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: つくば市、筑波大学
• [Presentation] ブタ単為発生胚を用いた凝集キメラ作出法 (2012)
  • Author(s): 中野和明、渡邊將人、松成ひとみ、松田泰輔、本田香澄、前原美樹、竹内靖浩、金井 貴博、新井良和、梅山一大、藤城修平、水上善久、長屋昌樹、花園豊、長嶋比呂志
  • Organizer: 第105回日本繁殖生物学会大会
  • Place of Presentation: つくば市、筑波大学
• [Presentation] In vitro modeling of alpha-1-antitrypsin deficiency using induced pluripotent stem cell-derived hepatocytes from alpha-1-antitrypsin deficient patients. (2012)
  • Author(s): Tafaleng EN, Han B, Hale P, Soto-Gutierrez A, Nagaya M, Duncan SA, Stols DB, Strom SC, Fox IJ
  • Organizer: The 63rd annual meeting of the American Association for the Study of Liver disease,
  • Place of Presentation: Boston, USA
• [Presentation] Development of a feasible verification system for pluripotent stem cells using porcine parthenogenetic embryos (2012)
  • Author(s): Nakano K, Watanabe M, Matsunari H, Matsuda T, Honda K, Maehara M, Kanai T, Arai Y, Umeyama K, Fujishiro S, Nagaya M, Nagaya M, Nagashima H
  • Organizer: 10th International Society for Stem Cell Research
  • Place of Presentation: Yokohama
• [Presentation] 遺伝子改変ブタ・クローンブタのトランスレーショナルリサーチへの応用
  • Author(s): 長嶋比呂志、松成ひとみ、中野和明、渡邊将人、梅山一大、長屋昌樹
  • Organizer: 日本実験動物医学会
  • Place of Presentation: 大分
  • Invited
• [Remarks] 明治大学バイオリソース研究国際インスティチュート
  • URL: http://muiibr.com/institute/institute.html
• [Patent(Industrial Property Rights)] 免疫抑制剤の評価方法、及び免疫抑制剤評価キット (2014)
  • Inventor(s): 長屋昌樹,長嶋比呂志
  • Industrial Property Rights Holder: 長屋昌樹,長嶋比呂志
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-027655
  • Filing Date: 2014-02-17
• [Patent(Industrial Property Rights)] 免疫抑制剤の評価方法、及び免疫抑制剤評価キット. (2014)
  • Inventor(s): 長屋昌樹, 長嶋比呂志
  • Industrial Property Rights Holder: 長屋昌樹, 長嶋比呂志
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-027655
  • Filing Date: 2014-02-17