Life-saving effect and mechanism of action of thrombopoietin receptor agonist in radiation-exposed individuals

• Project/Area Number: 25293256
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Hirosaki University
• Principal Investigator: KASHIWAKURA IKUO 弘前大学, 保健学研究科, 教授 (00177370)
• Co-Investigator(Kenkyū-buntansha): 吉野 浩教 弘前大学, 保健学研究科, 助教 (10583734) ; 門前 暁 弘前大学, 保健学研究科, 助教 (20514136) ; 伊藤 巧一 弘前大学, 保健学研究科, 教授 (90398579)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 被ばく医療 / TPO受容作動薬 / 造血幹細胞 / 急性放射性症候群 / TPO受容体作動薬 / 放射線防護剤 / 急性放射線症候群

Outline of Final Research Achievements

The following three points were cited as research targets
1) Establishment of an optimal administration method of a thrombopoietin (TPO) receptor agonist in radiation-exposed individuals 2) Elucidation of the mechanism of action of lethal evasion of agonists in radiation-exposed individuals 3) Verification of the occurrence of adverse events in radiation-exposed individuals using a TPO receptor agonist romiplostim (RP) as a life-saving agent by long-term observation
The planned schedule for 3 years from the start of the research was largely adhered to. Administration of RP is optimal for 3 days after radiation exposure. RP acts on immature hematopoietic stem cells and vital stem cells of the gastrointestinal tract to promote long-term radiation reduction and regeneration. No adverse events were observed in radiation-exposed individuals using RP. Thus, we suggest that RP acts on recovery and regeneration of the hematopoietic and gastrointestinal systems from radiation damage.

Research Products

• [Journal Article] Exosomes derived from SW480 colorectal cancer cells promote cell migration in HepG2 hepatocellular cancer cells via the mitogen-activated protein kinase pathway. (2016)
  • Author(s): M. Chiba , N. Watanabe , M. Watanabe , M. Sakamoto , A. Sato , M. Fujisaki , S. Kubota , S. Monzen , A. Maruyama , N. Nanashima , I. Kashiwakura , T. Nakamura .
  • Journal Title: International Journal of Oncology Volume: 48(1) Issue: 1 Pages: 305-312
  • DOI: 10.3892/ijo.2015.3255
  • Peer Reviewed / Open Access
• [Journal Article] Expression analysis of radiation-responsive genes in human hematopoietic stem/progenitor cells. (2016)
  • Author(s): T. Tsujiguchi , T. Hirouchi , S. Monzen , Y. Tabuchi , I. Takasaki , T. Kondo , I. Kashiwakura.
  • Journal Title: Journal of Radiation Research Volume: 57(1) Issue: 1 Pages: 35-43
  • DOI: 10.1093/jrr/rrv071
  • Peer Reviewed / Open Access
• [Journal Article] Radiomitigative Effects of Grifola frondosa Preparations on Mice Exposed to Lethal Ionizing Irradiation. (2016)
  • Author(s): K. Yokoyama, M. Yamaguchi, A. Nishiyama, S. Murakami, A. Tanaka, M. Hosoda, I. Kashiwakura.
  • Journal Title: Jacobs Journal of Food and Nutrition Volume: 2(3) Pages: 022-025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characteristics of human CD34+ cells exposed to ionizing radiation under cytokine-free conditions. (2015)
  • Author(s): J. Ishikawa, N. Hayashi, M. Yamaguchi, S. Monzen, I. Kashiwakura.
  • Journal Title: Journal of Radiation Research Volume: 56(4) Issue: 4 Pages: 678-690
  • DOI: 10.1093/jrr/rrv024
  • Peer Reviewed / Open Access
• [Journal Article] LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. (2015)
  • Author(s): M. Sato , K. Hirose , I. Kashiwakura , M. Aoki , H. Kawaguchi , Y. Hatayama , H. Akimoto , Y. Narita , Y. Takai.
  • Journal Title: Molecular Medicine Reports Volume: 2(3) Issue: 3 Pages: 3462-3468
  • DOI: 10.3892/mmr.2015.3862
  • Peer Reviewed / Open Access
• [Journal Article] Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation. (2015)
  • Author(s): T. Hirouchi, K. Ito, M. Nakano, S. Monzen, H. Yoshino, M. Chiba, M. Hazawa, A. Nakano, J. Ishikawa, M. Yamaguchi, K. Tanaka, I. Kashiwakura.
  • Journal Title: Current Pharmaceutical Biotechnology Volume: 17(2) Pages: 190-199
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of ionizing radiation on differentiation of murine bone marrow cells into mast cells. (2015)
  • Author(s): S. Murakami , H. Yoshino , J. Ishikawa, M. Yamaguchi , T. Tsujiguchi , A. Nishiyama , K. Yokoyama , I. Kashiwakura .
  • Journal Title: Journal of Radiation Research Volume: 56(6) Issue: 6 Pages: 865-871
  • DOI: 10.1093/jrr/rrv061
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of oxidative stress markers in plasma derived from individuals exposed to ionizing radiation (2015)
  • Author(s): A. Nishiyama, M. Yamaguchi, T. Tsujiguchi, S. Murakami, I. Kashiwakura
  • Journal Title: Experimental and Therapeutic Medicine Volume: in press
  • Peer Reviewed
• [Journal Article] Relationship between the regional cerebral blood flow and Mini-Mental State Examination score in patients with Alzheimer’s disease (2015)
  • Author(s): H. Saitou, M. Tsushima, Y. Mariya, I. Kashiwakura
  • Journal Title: Experimental and Therapeutic Medicine Volume: in press
  • Peer Reviewed
• [Journal Article] Effects of ionizing radiation on retinoic acid-inducible gene-I-like receptors (2015)
  • Author(s): H. Yoshino, T. Saitoh, M. Kozakai, I. Kashiwakura
  • Journal Title: Biomedical reports Volume: 3 (1) Issue: 1 Pages: 59-62
  • DOI: 10.3892/br.2014.377
  • Peer Reviewed
• [Journal Article] Ionizing radiation affects the expression of Toll-like receptors 2 and 4 in human monocytic cells through c-Jun N-terminal kinase activation (2014)
  • Author(s): H. Yoshino, K. Chiba, T. Saitoh, I. Kashiwakura
  • Journal Title: Journal of Radiation Research Volume: 55 (5) Issue: 5 Pages: 876-884
  • DOI: 10.1093/jrr/rru040
  • Peer Reviewed / Open Access
• [Journal Article] Long-lasting radioprotective effects of a combination of pharmaceutical drugs on the survival of mice exposed to lethal ionizing radiation (2014)
  • Author(s): M. Yamaguchi, T. Hirouchi, M. Nakano, S. Monzen, H. Yoshino, M. Chiba, J. Ishikawa, A. Nishiyama, S. Murakami, K. Ito and and I. Kashiwakura.
  • Journal Title: Radiat Emerg Med Volume: 3 Pages: 50-55
  • Peer Reviewed
• [Presentation] Thrombopoietin-Mimetic Romiplostim Confers the Complete Survival Rate to Mice Exposed to Lethal Ionizing Radiation. (2015)
  • Author(s): M. Yamaguchi, T. Hirouchi, M. Chiba, S. Monzen, H. Yoshino, J. Ishikawa, T. Tsujiguchi, A. Nishiyama, S. Murakami, J. Komura, I. Kashiwakura.
  • Organizer: 57th American Society of Hematology (ASH2015)
  • Place of Presentation: Orlande, USA.
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] 致死線量放射線ばく露マウスに対するc-mpl作動薬の作用. (2015)
  • Author(s): 山口 平, 廣内 篤久, 千葉 満, 門前 暁, 吉野 浩教, 小村 潤一郎, 柏倉 幾郎.
  • Organizer: 日本放射線影響学会第1回放射線ワークショップ-未来に繋ぐ放射線研究-
  • Place of Presentation: 富山大学五福キャンパス黒田講堂（富山県富山市）
  • Year and Date: 2015-10-16
• [Presentation] エルトロンボパグの放射線防護効果の探索. (2015)
  • Author(s): 横山 昂生, 山口 平, 辻口 貴清, 柏倉 幾郎.
  • Organizer: 日本放射線影響学会第1回放射線ワークショップ-未来に繋ぐ放射線研究-
  • Place of Presentation: 富山大学五福キャンパス黒田講堂（富山県富山市）
  • Year and Date: 2015-10-16
• [Presentation] RIG-I様受容体アゴニストと放射線の併用による抗腫瘍効果増強． (2015)
  • Author(s): 吉野 浩教, 柏倉 幾郎.
  • Organizer: 日本放射線影響学会第1回放射線ワークショップ-未来に繋ぐ放射線研究-
  • Place of Presentation: 富山大学五福キャンパス黒田講堂（富山県富山市）
  • Year and Date: 2015-10-16
• [Presentation] Effects of a c-mpl agonist on mice exposed to lethal ionizing radiation. (2015)
  • Author(s): M. Yamaguchi, T. Hirouchi, M. Chiba, S. Monzen, H. Yoshino, J. Ishikawa, T. Tsujiguchi, A. Nishiyama, S. Murakami, J. Komura, I. Kashiwakura.
  • Organizer: 15th International Congress of Radiation Research (ICRR)
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] Expression analysis of c-Myc in bone marrow cells of mice exposed to ionizing radiation. (2015)
  • Author(s): K. Yokoyama, A. Nishiyama, T. Tsujiguchi, S. Murakami, M. Yamaguchi, I. Kashiwakura.
  • Organizer: 15th International Congress of Radiation Research (ICRR)
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] Up-regulated and Down-regulated Cis-natural Antisense Transcripts in the Human B Lymphoblastic Cells after X-ray Irradiation. (2015)
  • Author(s): M. Chiba, S. Monzen, I. Kashiwakura, T.Nakamura.
  • Organizer: 15th International Congress of Radiation Research (ICRR)
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] Effects of a c-mpl agonist on mice exposed to lethal ionizing radiation. (2015)
  • Author(s): M. Yamaguchi, T. Hirouchi, M. Chiba, S. Monzen, H. Yoshino, J. Ishikawa, T. Tsujiguchi, A. Nishiyama, S. Murakami, J. Komura, I. Kashiwakura.
  • Organizer: 2st Educational Symposium on Radiation and Health by young scientists (ESRAH2015)
  • Place of Presentation: 弘前大学保健学研究科（青森県弘前市）
  • Year and Date: 2015-05-23
  • Int'l Joint Research
• [Presentation] Expression analysis of c-Myc in bone marrow cells of mice exposed to ionizing radiation. (2015)
  • Author(s): K. Yokoyama, A. Nishiyama, T. Tsujiguchi, S. Murakami, M. Yamaguchi, I. Kashiwakura.
  • Organizer: 2st Educational Symposium on Radiation and Health by young scientists (ESRAH2015)
  • Place of Presentation: 弘前大学保健学研究科（青森県弘前市）
  • Year and Date: 2015-05-23
  • Int'l Joint Research
• [Presentation] Serum MicroRNAs as Potential Biomarkers in Mice Exposed to Ionizing Radiation. (2015)
  • Author(s): M. Chiba, S. Monzen, I. Kashiwakura, T.Nakamura.
  • Organizer: 2st Educational Symposium on Radiation and Health by young scientists (ESRAH2015)
  • Place of Presentation: 弘前大学保健学研究科（青森県弘前市）
  • Year and Date: 2015-05-23
  • Int'l Joint Research
• [Presentation] 致死線量放射線ばく露マウスに対するc-Mpl作動薬の作用 (2014)
  • Author(s): 山口 平，廣内 篤久，石川 純也，辻口 貴清，西山 彩香，村上 翔，小村 潤一郎，柏倉 幾郎
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 電離放射線曝露マウス骨髄有核細胞におけるMyc遺伝子発現の解析 (2014)
  • Author(s): 西山 彩香，辻口 貴清，山口 平，村上 翔，柏倉 幾郎
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 致死線量放射線ばく露マウスへの国内承認医薬品の投与効果 (2014)
  • Author(s): 山口 平，廣内 篤久，石川 純也，西山 彩香，村上 翔，柏倉 幾郎
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Effects of a c-mpl Receptor Agonist on Mice Exposed to Lethal Ionizing Radiation (2014)
  • Author(s): M. Yamaguchi, T. Hirouchi, M. Chiba, S. Monzen, H. Yoshino, J. Ishikawa, T. Tsujiguchi, A, Nishiyama, S, Murakami, J. Komura, I. Kashiwakura
  • Organizer: The 9th International Symposium on the Natural Radiation Environment
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-22 – 2014-09-26
• [Presentation] Effects of ionizing radiation on retinoic acid-inducible gene-I-like receptors (2014)
  • Author(s): H. Yoshino, T. Saitoh, M. Kozakai, I. Kashiwakura
  • Organizer: The 9th International Symposium on the Natural Radiation Environment
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-22 – 2014-09-26
• [Presentation] Expression analysis of radiation responsive genes in human hematopoietic stem/progenitor cells (2014)
  • Author(s): T. Tsujiguchi, T. Hirouchi, S. Monzen, Y. Tabuchi, I. Takasaki, T. Kondo, I. Kashiwakura
  • Organizer: The 1st Educational Symposium on RADIATION AND HEALTH by Young Scientists
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-21 – 2014-09-22
• [Presentation] Evaluation of oxidative stress markers in plasma derived from individuals exposed to ionizing radiation (2014)
  • Author(s): A. Nishiyama, M. Yamaguchi, T. Tsujiguchi, S. Murakami, I. Kashiwakura
  • Organizer: The 1st Educational Symposium on RADIATION AND HEALTH by Young Scientists
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-21 – 2014-09-22
• [Presentation] Effects of ionizing radiation on differentiation and induction of murine bone marrow-derived mast cells (2014)
  • Author(s): S. Murakami, H. Yoshino, J. Ishikawa, M. Yamaguchi, T. Tsujiguchi, A. Nishiyama, K. Yokoyama, I. Kashiwakura
  • Organizer: The 1st Educational Symposium on RADIATION AND HEALTH by Young Scientists
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-21 – 2014-09-22
• [Presentation] Long-lasting radioprotective effects of a combination of pharmaceutical drugs on the survival of mice exposed to lethal ionizing radiation (2014)
  • Author(s): K. Yokoyama, T. Hirouchi, M. Yamaguchi, A. Nishiyama, S. Murakami, I. Kashiwakura
  • Organizer: The 1st Educational Symposium on RADIATION AND HEALTH by Young Scientists
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2014-09-21 – 2014-09-22
• [Presentation] ヒト肺がん細胞のウイルス核酸認識受容体の応答性に及ぼす放射線の影響 (2014)
  • Author(s): 吉野 浩教，柏倉 幾郎
  • Organizer: 第43回制癌シンポジウム・ 第52回生物部会学術大会
  • Place of Presentation: メルパルク京都（京都府京都市）
  • Year and Date: 2014-07-11 – 2014-07-12
• [Presentation] マウス骨髄細胞由来肥満細胞の分化・増殖に対する放射線の影響 (2014)
  • Author(s): 村上 翔，吉野 浩教，山口 平，西山 彩香，横山 昂生，柏倉 幾郎
  • Organizer: 第43回制癌シンポジウム・ 第52回生物部会学術大会
  • Place of Presentation: メルパルク京都（京都府京都市）
  • Year and Date: 2014-07-11 – 2014-07-12
• [Presentation] 致死線量放射線ばく露マウスに対するC-Mpl作動薬の作用
  • Author(s): 石川純也，廣内篤久，伊藤巧一，千葉満，中野学，門前暁，吉野浩教，羽澤勝治，中野光，山口平，田中公夫，柏倉幾郎
  • Organizer: 日本放射線影響学会第56回大会
  • Place of Presentation: 青森市
• [Remarks] 弘前大学大学院柏倉研究室
  • URL: http://www.hs.hirosaki-u.ac.jp/~kashiwakura/
• [Remarks] 柏倉研究室
  • URL: http://www.hs.hirosaki-u.ac.jp/~kashiwakura/
• [Remarks] 柏倉研究室HP
  • URL: http://www.hs.hirosaki-u.ac.jp/~kashiwakura/