The impact of hemoxygenase-1 (HO-1) on the treatment outocome after bone marrow transplantation and the possibility of HO-1 as a new therapeutic target

• Project/Area Number: 15K08643
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kanazawa University
• Principal Investigator: MORISHITA Eriko 金沢大学, 保健学系, 教授 (50251921)
• Co-Investigator(Kenkyū-buntansha): 谷内江 昭宏 金沢大学, 医学系, 教授 (40210281)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 造血幹細胞移植 / 移植後合併症 / ヘムオキシゲナーゼ-１(HO-1) / 一塩基置換 / Fc receptor-like 3遺伝子 / タクロリムス（ＦＫ506） / 遺伝子組換えトロンボモジュリン / 移植片対宿主病 / 血管内皮障害 / FCRL3 / 移植予後 / タクロリムス / 血管内皮細胞 / トロンボモジュリン / アンギオポエチン-1 / 相血幹細胞移植 / 組織因子 / HO-1 / サイトカイン / スタチン

Outline of Final Research Achievements

We investigated the impact of the Fc receptor-like 3 variant（s3761959） on transplantation outcomes in a cohort of 1029 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. We revealed that the recipient T/T genotype was associated with significantly better overall survival rates and a lower incidence of treatment-related death than the recipient C/C or C/T genotype.
Tacrolimus (FK506) calcineurin inhibitor is an effective immunosuppressant which is essential to prevent allograft rejection. We showed that FK506 impaired the function of coagulation and fibrinolytic systems and permeability in the human umbilical endothelial cells in vitro. Moreover, pre-treatment of recombinant thrombomodulin prevented these endothelial dysfunction.

Research Products

• [Journal Article] Gene analysis of inherited antithrombin deficiency and functional analysis of abnormal antithrombin protein (N87D) (2018)
  • Author(s): Kamijima S, Sekiya A, Takata M, Nakano H, Murakami M, Nakazato T, Asakura H, Morishita E
  • Journal Title: Int J Hematol Volume: 107 Issue: 4 Pages: 490-494
  • DOI: 10.1007/s12185-017-2352-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnosis and treatment of inherited thrombophilia (2017)
  • Author(s): 森下 英理子
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 7 Pages: 866-874
  • DOI: 10.11406/rinketsu.58.866
  • NAID: 130005907636
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Aortic Aneurysm-associated Disseminated Intravascular Coagulation that Responded Well to a Switch from Warfarin to Rivaroxaban (2017)
  • Author(s): Kadohira Y, Yamada S, Matsuura E, Hayashi T, Morishita E, Nakao S, Asakura H
  • Journal Title: Internal Medicine Volume: 56 Issue: 21 Pages: 2913-2917
  • DOI: 10.2169/internalmedicine.8666-16
  • NAID: 130006191957
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Factor XI deficiency as a result of a novel Tyr347Stop nonsense mutation in an elderly Japanese woman (2017)
  • Author(s): Ando Jun、Masuda Azuchi、Iizuka Kazuhide、Ochiai Tomonori、Shingai Naoki、Yasuda Hajime、Homma Yasuhiro、Kobayashi Erina、Morishita Eriko、Komatsu Norio
  • Journal Title: Geriatr Gerontol Int Volume: 17 Issue: 6 Pages: 1029-1031
  • DOI: 10.1111/ggi.13000
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome (2017)
  • Author(s): Sugiura-Ogasawara Mayumi、Omae Yosuke、Kawashima Minae、Toyo-Oka Licht、Khor Seik-Soon、Sawai Hiromi、Horita Tetsuya、Atsumi Tatsuya、Murashima Atsuko、Fujita Daisuke、Fujita Tomio、Morimoto Shinji、Morishita Eriko、Katsuragi Shinji、Kitaori Tamao、Katano Kinue、Ozaki Yasuhiko、Tokunaga Katsushi
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 9 Pages: 831-838
  • DOI: 10.1038/jhg.2017.46
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 深部静脈血栓症・肺塞栓症の発症機序と危険因子 (2017)
  • Author(s): 森下英理子
  • Journal Title: 日本医師会雑誌 Volume: 146 Pages: 22-26
• [Journal Article] 動脈・静脈の疾患（上）－最近の診断・治療動向－静脈疾患の検査 (2017)
  • Author(s): 森下英理子
  • Journal Title: 日本臨床 Volume: 75（増刊号4） Pages: 196-200
• [Journal Article] Gene analysis of six cases of congenital protein S deficiency and functional analysis of protein S mutations (A139V, C449F, R451Q, C475F, A525V and D599TfsTer13） (2017)
  • Author(s): Taniguchi F, Morishita E, Sekiya A, Nomoto H, Katsu S, Kaneko S, Asakura H, Ohtake S
  • Journal Title: Thromb Res Volume: 151 Pages: 8-16
  • DOI: 10.1016/j.thromres.2016.12.018
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Causative genetic mutations for antithrombin deficiency and their clinical background among Japanese patients. (2017)
  • Author(s): Sekiya A, Taniguchi F, Yamaguchi D, Kamijima S, Kaneko S, Katsu S, Hanamura M, Takata M, Nakano H, Asakura H, Ohtake S, Morishita E
  • Journal Title: Int J Hematol Volume: 105 Issue: 3 Pages: 287-294
  • DOI: 10.1007/s12185-016-2142-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thrombosis Prediction Based on Reference Ranges of Coagulation-Related Markers in Different Stages of Pregnancy. (2017)
  • Author(s): Sekiya A, Hayashi T, Kadohira Y, Shibayama M, Tsuda T, Jin X, Nomoto H, Asakura H, Wada T, Ohtake S, Morishita E
  • Journal Title: Clin Appl Thromb Hemost Volume: 印刷中 Issue: 7 Pages: 844-850
  • DOI: 10.1177/1076029616673732
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy (2016)
  • Author(s): Kagami K, Yamazaki R, Minami T, Okumura N, Morishita E, Fujiwara H
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 6 Pages: 722-725
  • DOI: 10.1111/jog.12972
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. (2016)
  • Author(s): Miyasaka N, Miura O, Kawaguchi T, Arima N, Morishita E, Usuki K, Morita Y, Nishiwaki K, Ninomiya H, Gotoh A, Imashuku S, Urabe A, Shichishima T, Nishimura J, Kanakura Y.
  • Journal Title: Int J Hematol Volume: 103 Issue: 6 Pages: 703-712
  • DOI: 10.1007/s12185-016-1946-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. (2016)
  • Author(s): Miyasaka N, Miura O, Kawaguchi T, Arima N, Morishita E, Usuki K, Morita Y, Nishiwaki K, Ninomiya H, Gotoh A, Imashuku S, Urabe A, Shichishima T, Nishimura JI, Kanakura Y.
  • Journal Title: Int J Hematol Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fluvastatin Upregulates the Expression of Tissue Factor Pathway Inhibitor in Human Umbilical Vein Endothelial Cells (2015)
  • Author(s): Sekiya A, Morishita E, Maruyama K, Torishima H, Ohtake S.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 22 Issue: 7 Pages: 660-668
  • DOI: 10.5551/jat.28175
  • NAID: 130005089136
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Late onset thrombosis in two Japanese patients with compound heterozygote protein S deficiency. (2015)
  • Author(s): Taniguchi F, Morishita E, Sekiya A, Yamaguchi D, Nomoto H, Kobayashi E, Takata M, Kosugi I, Takeuchi N, Asakura H, Ohtake S.
  • Journal Title: Thromb Res Volume: in press Issue: 6 Pages: 1221-1223
  • DOI: 10.1016/j.thromres.2015.03.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation. (2015)
  • Author(s): Nomoto H, Takami A, Espinoza JL, Matsuo K, Mizuno S, Onizuka M, Kashiwase K, Morishima Y, Fukuda T, Kodera Y, Doki N, Miyamura K, Mori T, Nakao S, Ohtake S, Morishita E
  • Journal Title: Int J Hematol Volume: 102 Issue: 4 Pages: 460-470
  • DOI: 10.1007/s12185-015-1867-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ELISA-based detection system for protein S K196E mutation, a genetic risk factor for venous thromboembolism (2015)
  • Author(s): Maruyama K, Akiyama M, Kokame K, Sekiya A, Morishita E, Miyata T
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0133196-e0133196
  • DOI: 10.1371/journal.pone.0133196
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnosis and treatment of microangiopathic hemolytic anemia (2015)
  • Author(s): 森下英理子
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 7 Pages: 795-806
  • DOI: 10.11406/rinketsu.56.795
  • NAID: 130005093105
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] 血栓止血性疾患の遺伝子診断－血栓性疾患 (2015)
  • Author(s): 森下英理子
  • Journal Title: 日本血栓止血学会誌 Volume: 26 Pages: 518-523
  • NAID: 130005102997
  • Peer Reviewed
• [Journal Article] 先天性血栓性素因の診断. (2015)
  • Author(s): 森下英理子
  • Journal Title: 日本検査血液学会雑誌 Volume: 16 Pages: 1-10
• [Presentation] Possible therapeutics for antiphospholipid antibody related thrombocytopenia: A systemic review and meta-analysis. (2017)
  • Author(s): Abe N, Oku K, Amengual O, Fujieda Y, Kato M, Bohgaki T, Yasuda S, Mori R, Morishita E, Suzuki-Inoue K, Atsumi T.
  • Organizer: The American College of Rheumatology/Association of Rheumatology Health Professionals 2017 annual meeting.
  • Int'l Joint Research
• [Presentation] Asymptomatic Dysprothrombinemia (Prothtombin Himi) with p.M380T and p.R431H Shows Severely Reduced Clotting Activity, Moderate Antithrombin Resistance and Severe Thrombomodulin Binding Defect (2016)
  • Author(s): Morishita E, Takata M, Akiyama M, Miyata T, Takagi A, Kojima T, Sekiya A, Taniguchi
  • Organizer: 58th American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 血栓止血領域の診療ガイド．先天性血栓性素因 (2016)
  • Author(s): 森下英理子
  • Organizer: 第78回日本血液学会学術集会(シンポジウム）
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 静脈血栓症の成因と治療 (2016)
  • Author(s): 森下英理子
  • Organizer: 第17回日本検査血液学会学術集会
  • Place of Presentation: 福岡国際会議場(福岡県福岡市）
  • Year and Date: 2016-08-06
  • Invited
• [Presentation] 先天性血栓性素因 (2016)
  • Author(s): 森下英理子
  • Organizer: 第38回日本血栓止血学会学術集会（教育講演）
  • Place of Presentation: 奈良春日野国際フォーラム甍（奈良県奈良市）
  • Year and Date: 2016-06-16
• [Presentation] 「特発性血栓症（先天性血栓性素因による）」の「指定難病」認定に向けての取り組み (2016)
  • Author(s): 森下英理子
  • Organizer: 第10回日本血栓止血学会学鬱標準化委員会（SSC)シンポジウム
  • Place of Presentation: 野村カンファレンスプラザ日本橋（東京都中央区）
  • Year and Date: 2016-02-20
  • Invited
• [Presentation] 血栓症の基礎と治療－先天性血栓性素因と悪性腫瘍に伴う血栓症ー (2016)
  • Author(s): 森下英理子
  • Organizer: 血栓症Total Manegement
  • Place of Presentation: 札幌第一三共式会社セミナー室（北海道札幌市）
  • Year and Date: 2016-02-05
  • Invited
• [Presentation] 血液凝固異常の検査の進め方 (2015)
  • Author(s): 森下英理子
  • Organizer: 第3回北陸血栓止血検査研究会
  • Place of Presentation: 金沢大学附属病院宝ホール（石川県金沢市）
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] 静脈血栓塞栓症の成因と治療―悪性腫瘍ならびに先天性血栓性素因を中心にー (2015)
  • Author(s): 森下英理子
  • Organizer: 第14回千葉循環器クリニカルフロンティア
  • Place of Presentation: ホテルオークラ千葉（千葉県千葉市）
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] 静脈血栓症の成因と治療 (2015)
  • Author(s): 森下英理子
  • Organizer: あきた凝固線溶セミナー
  • Place of Presentation: 秋田ビューホテル（秋田県秋田市）
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] トロンボモジュリンと血管内皮傷害 (2015)
  • Author(s): 森下英理子
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢市アートホール（石川県金沢市）
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] なぜできる！？静脈血栓症 (2015)
  • Author(s): 森下英理子
  • Organizer: 世界血栓症デー日本・市民公開講座2015
  • Place of Presentation: 御堂会館（大阪府大阪市）
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] Development of ELISA system for detection of Protein S K196E mutation, a genetic risk factor for venous thromboembolism. (2015)
  • Author(s): Keiko Maruyama, Masashi Akiyama, Koichi Kokame, Akiko Sekiya, Eriko Morishita, Toshiyuki Miyata
  • Organizer: 2015 International Society on Thormbosis and Haemostasis
  • Place of Presentation: the Metro Toronto Convention Center (Toronto, Canada))
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] 先天性プロテインS・プロテインC欠損症の遺伝子診断ならびに臨床所見 (2015)
  • Author(s): 森下英理子
  • Organizer: 第37回日本血栓止血学会学術セミナー
  • Place of Presentation: 甲府総合市民会館（山梨県甲府市）
  • Year and Date: 2015-05-21
  • Invited
• [Book] むかしの頭で診ていませんか？血液診療をスッキリまとめました (2017)
  • Author(s): 森下英理子
  • Total Pages: 202
  • Publisher: 南江堂
• [Book] 血液疾患最新の治療2017-2019 (2017)
  • Author(s): 森下英理子
  • Total Pages: 370
  • Publisher: 南江堂
• [Book] 動脈・静脈の疾患（上）－最近の診断・治療動向－ (2017)
  • Author(s): 森下英理子
  • Publisher: 日本臨床
• [Book] 新・血栓止血血管学 凝固と炎症 (2015)
  • Author(s): 森下英理子
  • Total Pages: 189
  • Publisher: 金芳堂