Activation mechanism of 12-Lypoxigenase in thrombus formation

• Project/Area Number: 19K08853
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: Katsumi Akira 国立研究開発法人国立長寿医療研究センター, 病院, 部長 (80378025)
• Co-Investigator(Kenkyū-buntansha): 天野 睦紀 名古屋大学, 医学系研究科, 准教授 (90304170)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アラキドン酸 / small GTPase / エフェクター / ALOX / 脂質メディエーター / 血栓症 / Rho GTPase / 血栓形成 / Rho ファミリー / フォルミン / 12-リポキシゲナーぜ / RhoA

Outline of Research at the Start

血小板におけるアゴニスト受容体からのシグナルは Gα13を介して低分子量GTPase RhoAを活性化する。その結果血小板の形態変化、濃染顆粒 内容物の分泌をおこす。我々はアフィニティクロマトグラフィーにより活性化RhoA がフォルミンDaam1を介して12-リポキシゲナーゼ(12-LOX)に結合することを見いだした。 12-LOXは主に血小板に発現し、アラキドン酸からの12-ヒドロキシエイコサテトラエン酸 (12-HETE)等の脂質メディエーター合成を介して血小板凝集を惹起する。本研究では活性化RhoA-Daam1が、12-LOXの細胞膜への局在を誘導し活性を制御することを証明する。

Outline of Final Research Achievements

Lipoxygenase (LOX) is a multifunctional protein involved in atherosclerosis, platelet aggregation, chronic inflammation, and cancer development. We established an affinity chromatography system using Rho family GTPases as bait followed by mass spectrometry (LC/MS-MS) and identified several proteins that bind specifically to the active form of Rho GTPase. Among them, 12-LOX was confirmed to bind to active Rho GTPases. There was no direct binding between the two, indicating that 12-LOX binds to active Rho GTPases via their effectors, and experiments with GTPase inhibitors revealed activation-dependent binding of 12-LOX.

Academic Significance and Societal Importance of the Research Achievements

アラキドン酸リポキシゲナーゼ(LOX)とその下流の脂質メディエーターは動脈硬化、血小板凝集、慢性炎症、がんの進展などに関与する多機能蛋白である。LOX下流の脂質メディエーターについては活発に研究が行われているが、上流の制御メカニズムについては殆ど報告がなされていない。当該研究ではALOX上流の制御メカニズムを解明することで、血管をターゲットにした治療応用の基盤としたい。

Research Products

• [Journal Article] The usefulness of tranexamic acid for bleeding symptoms of chronic consumptive coagulopathy complicated by aortic disease: a single-institute, retrospective study of 14 patients (2023)
  • Author(s): Suzuki N, Suzuki N, Kawaguchi Y, Okamoto S, Kanematsu T, Katsumi A, Suzuki A, Tamura S, Kojima T, Kiyoi H, Matsushita T.
  • Journal Title: Thromb J Volume: 21 Issue: 1 Pages: 10-10
  • DOI: 10.1186/s12959-022-00429-4
  • Peer Reviewed / Open Access
• [Journal Article] VWF-Gly2752Ser, a novel non-cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C-terminal dimer formation (2022)
  • Author(s): Okamoto S, Tamura S, Sanda N, Odaira K, Hayakawa Y, Mukaide M, Suzuki A, Kanematsu T, Hayakawa F, Katsumi A, Kiyoi H, Kojima T, Matsushita T, Suzuki N.
  • Journal Title: J Thromb Haemost Volume: 20 Issue: 8 Pages: 1784-1796
  • DOI: 10.1111/jth.15746
  • Peer Reviewed / Open Access
• [Journal Article] F9 mRNA splicing aberration due to a deep Intronic structural variation in a patient with moderate hemophilia B (2022)
  • Author(s): Odaira Koya、Kawashima Fumika、Tamura Shogo、Suzuki Nobuaki、Tokoro Mahiru、Hayakawa Yuri、Suzuki Atsuo、Kanematsu Takeshi、Okamoto Shuichi、Takagi Akira、Katsumi Akira、Matsushita Tadashi、Shima Midori、Nogami Keiji、Kojima Tetsuhito、Hayakawa Fumihiko
  • Journal Title: Thrombosis Research Volume: 213 Pages: 91-96
  • DOI: 10.1016/j.thromres.2022.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Periosteum-derived podoplanin-expressing stromal cells regulate nascent vascularization during epiphyseal marrow development (2022)
  • Author(s): Tamura Shogo、Mukaide Masato、Katsuragi Yumi、Fujii Wataru、Odaira Koya、Suzuki Nobuaki、Tsukiji Nagaharu、Okamoto Shuichi、Suzuki Atsuo、Kanematsu Takeshi、Katsumi Akira、Takagi Akira、Ikeda Katsuhide、Ueyama Jun、Hirayama Masaaki、Suzuki-Inoue Katsue、Matsushita Tadashi、Kojima Tetsuhito、Hayakawa Fumihiko
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 5 Pages: 101833-101833
  • DOI: 10.1016/j.jbc.2022.101833
  • Peer Reviewed / Open Access
• [Journal Article] Protein S-Leu17Pro disrupts the hydrophobicity of its signal peptide causing a proteasome-dependent degradation (2022)
  • Author(s): Okada K, Tamura S, Suzuki N, Odaira K, Mukaide M, Fujii W, Katsuragi Y, Suzuki A, Kanematsu T, Okamoto S, Suzuki N, Katsumi A, Matsushita T, Kojima T, Hayakawa F.
  • Journal Title: Thromb Res Volume: 210 Pages: 26-32
  • DOI: 10.1016/j.thromres.2021.12.014
  • Peer Reviewed
• [Journal Article] Development and validation of a novel qualitative test for plasma fibrinogen utilizing clot waveform analysis (2022)
  • Author(s): Suzuki Atsuo、Suzuki Nobuaki、Kanematsu Takeshi、Shinohara Sho、Kurono Hiroshi、Arai Nobuo、Okamoto Shuichi、Suzuki Naruko、Tamura Shogo、Kikuchi Ryosuke、Katsumi Akira、Kojima Tetsuhito、Matsushita Tadashi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 434-434
  • DOI: 10.1038/s41598-021-04464-5
  • Peer Reviewed / Open Access
• [Journal Article] Elevated red blood cell distribution width is associated with poor outcome in osteoporotic vertebral fracture (2021)
  • Author(s): Sakai Yoshihito、Wakao Norimitsu、Matsui Hiroki、Watanabe Tsuyoshi、Iida Hiroki、Katsumi Akira
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: 39 Issue: 6 Pages: 1048-1057
  • DOI: 10.1007/s00774-021-01242-1
  • Peer Reviewed
• [Journal Article] Anemia in older adults as a geriatric syndrome: A review (2021)
  • Author(s): Katsumi Akira、Abe Akihiro、Tamura Shogo、Matsushita Tadashi
  • Journal Title: Geriatrics & Gerontology International Volume: 21 Issue: 7 Pages: 549-554
  • DOI: 10.1111/ggi.14183
  • Peer Reviewed
• [Journal Article] Essential role of a carboxyl-terminal α-helix motif in the secretion of coagulation factor XI. (2021)
  • Author(s): Hayakawa Y, Tamura S, Suzuki N, Odaira K, Tokoro M, Kawashima F, Hayakawa F, Takagi A, Katsumi A, Suzuki A, Okamoto S, Kanematsu T, Matsushita T, Kojima T.
  • Journal Title: J Thromb Haemost. Volume: - Issue: 4 Pages: 920-930
  • DOI: 10.1111/jth.15242
  • Peer Reviewed / Open Access
• [Journal Article] Myh9 R702C is associated with erythroid abnormality with splenomegaly in mice (2021)
  • Author(s): Kanematsu T, Suzuki N, Tamura S, Suzuki A, Ishikawa Y, Katsumi A, Kiyoi H, Saito H, Kunishima S, Kojima T, Matsushita T.
  • Journal Title: Nagoya Journal of Medical Science Volume: 83 Issue: 1 Pages: 75-86
  • DOI: 10.18999/nagjms.83.1.75
  • NAID: 120007127313
  • ISSN: 0027-7622
  • URL: https://nagoya.repo.nii.ac.jp/records/2000205
  • Peer Reviewed / Open Access
• [Journal Article] Impact of variation in reagent combinations for one‐stage clotting assay on assay discrepancy in nonsevere haemophilia A (2020)
  • Author(s): Suzuki Atsuo、Suzuki Nobuaki、Kanematsu Takeshi、Okamoto Shuichi、Tamura Shogo、Kikuchi Ryosuke、Katsumi Akira、Kiyoi Hitoshi、Kojima Tetsuhito、Matsushita Tadashi
  • Journal Title: International Journal of Laboratory Hematology Volume: 43 Issue: 1 Pages: 131-138
  • DOI: 10.1111/ijlh.13335
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A (2020)
  • Author(s): Tokoro Mahiru、Tamura Shogo、Suzuki Nobuaki、Kakihara Misaki、Hattori Yuna、Odaira Koya、Suzuki Sachiko、Takagi Akira、Katsumi Akira、Hayakawa Fumihiko、Okamoto Shuichi、Suzuki Atsuo、Kanematsu Takeshi、Matsushita Tadashi、Kojima Tetsuhito
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 8 Issue: 9 Pages: 1-12
  • DOI: 10.1002/mgg3.1390
  • Peer Reviewed / Open Access
• [Journal Article] Higher FVIII:C Measured by Chromogenic Substrate Assay Than by One-Stage Assay Is Associated With Silent Hemophilic Arthropathy (2020)
  • Author(s): Mika Ogawa, Nobuaki Suzuki, Nobunori Takahashi, Shogo Tamura, Atsuo Suzuki, Sachiko Suzuki, Yuua Hattori, Misaki Kakihara, Takeshi Kanematsu, Toshihisa Kojima, Akira Katsumi, Fumihiko Hayakawa, Tetsuhito Kojima, Naoki Ishiguro , Hitoshi Kiyoi , Tadashi Matsushita
  • Journal Title: Thromb Res Volume: 188 Pages: 103-105
  • DOI: 10.1016/j.thromres.2020.01.003
  • NAID: 120006872431
  • Peer Reviewed / Open Access
• [Journal Article] Truncated RUNX1 generated from the fusion of RUNX1 to antisense GRIK2 via a cryptic chromosome translocation enhances sensitivity to granulocyte colony-stimulating factor (2020)
  • Author(s): Abe A, Yamamoto Y, Katsumi A, Yamamoto H, Okamoto A, Inaguma Y, Iriyama C, Tokuda M, Okamoto M, Emi N, Tomita A.
  • Journal Title: Cytogenetic and Genome Research Volume: - Issue: 5 Pages: 255-263
  • DOI: 10.1159/000508012
  • Peer Reviewed / Open Access
• [Journal Article] Apparent Synonymous Mutation F9 c.87A>G Causes Secretion Failure by In-Frame Mutation With Aberrant Splicing (2019)
  • Author(s): Odaira K, Tamura S, Suzuki N, Kakihara M, Hattori Y, Tokoro M, Suzuki S, Takagi A, Katsumi A, Hayakawa F, Okamoto S, Suzuki A, Kanematsu T, Matsushita T, Kojima T.
  • Journal Title: Thromb Res Volume: 179 Pages: 95-103
  • DOI: 10.1016/j.thromres.2019.04.022
  • Peer Reviewed / Open Access
• [Journal Article] Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency (2019)
  • Author(s): Tamura Shogo、Hashimoto Erika、Suzuki Nobuaki、Kakihara Misaki、Odaira Koya、Hattori Yuna、Tokoro Mahiru、Suzuki Sachiko、Takagi Akira、Katsumi Akira、Hayakawa Fumihiko、Suzuki Atsuo、Okamoto Shuichi、Kanematsu Takeshi、Matsushita Tadashi、Kojima Tetsuhito
  • Journal Title: Thrombosis Research Volume: 178 Pages: 159-170
  • DOI: 10.1016/j.thromres.2019.04.004
  • Peer Reviewed / Open Access
• [Presentation] Periosteum-derived podoplanin-expressing stromal cells populate the epiphyseal bone marrow (2022)
  • Author(s): 桂木 裕実、田村 彰吾、向出 将人、藤井 渉、大平 晃也、鈴木 伸明、築地 長治、岡本 修一、鈴木 敦夫、兼松 毅、勝見 章、高木 明、鈴木 克枝、松下 正、小嶋 哲人、早川 文彦
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Clinical observation study of AML, MDS and CMML in Japan Adult Leukemia Study Group (JALSG-CS-11) (2022)
  • Author(s): 臼杵 憲祐、大竹 茂樹、石川 裕一、松村 到、勝見 章、清井 仁、宮崎 泰司など
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] 先天性アンチトロンビン欠乏症に同定した新規SERPINC1変異（AT-I218F）の分子病態解析 (2022)
  • Author(s): 藤井渉、田村彰吾、鈴木伸明、向出将人、桂木裕実、鈴木敦夫、兼松毅、岡本修一、鈴木奈瑠子、勝見 章、小嶋哲人、松下正、早川文彦
  • Organizer: 第44回日本血栓止血学会学術集会
• [Presentation] がん関連血栓症の治療（本邦と欧米のエビデンスの現状）シンポジウム４ (2021)
  • Author(s): 勝見 章
  • Organizer: 第4回日本腫瘍循環器学会学術集会 2021/10/12 仙台
• [Presentation] Outcomes of SCT for MDS pts registered in a prospective observational study; JALSG-CS-11-MDS-SCT (2021)
  • Author(s): Noriharu Nakagawa，Ken Ishiyama, Kensuke Usuki, Akira Katsumi， Hitoshi Kiyoi， Itaru Matsumura， Yasushi Miyazaki et al.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Immunosuppressive therapy for aplastic anemia in the elderly (2021)
  • Author(s): Sonoko Kamoshita，Akira Katsumi
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] 当センターにおける静脈血栓塞栓症発症の危険因子 (2020)
  • Author(s): 勝見 章，室谷健太、鴨下園子、伊藤美由紀、松下 正、小嶋哲人
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 高齢者における静脈血栓塞栓症発症の症例対照研究 (2020)
  • Author(s): 勝見 章、室谷 健太、鴨下 園子、伊藤 美由紀、田村 彰吾、鈴木 伸明、松下 正、小嶋 哲人
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] Template switchingによるF8エクソン15欠損が認められた重症血友病A症例 (2020)
  • Author(s): 所 真昼, 田村 彰吾, 鈴木 伸明, 大平 晃也, 河島 史華, 早川 友梨, 早川 文彦, 岡本 修一, 兼松 毅, 勝見 章, 松下 正, 小嶋 哲人
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] 当センターにおける静脈血栓塞栓症の発症率推計 (2019)
  • Author(s): 勝見 章、室谷健太、池野世新、渡辺 浩、松下 正、小嶋哲人
  • Organizer: 第61回日本老年医学会学術集会
• [Presentation] 当センターにおける静脈血栓塞栓症の発症率推計 (2019)
  • Author(s): 勝見 章、伊藤美由紀、鴨下園子、池野世新、渡辺 浩、室谷健太、松下 正、小嶋哲人
  • Organizer: 第41回日本血栓止血学会学術集会
• [Presentation] トロンビンNa binding regionのミスセンス変異は多くがアンチトロンビン抵抗性を示すが、凝固活性も低下する (2019)
  • Author(s): 田村彰吾、川上萌、勝見 章、高木 明、早川文彦 、小嶋哲人
  • Organizer: 第13回日本血栓止血学会学術標準化委員会（SSC）シンポジウム
• [Presentation] MYH9異常症が赤血球造血にもたらす影響の検討 (2019)
  • Author(s): 兼松 毅, 鈴木 伸明, 鈴木 敦夫, 田村 彰吾, 岡本 修一, 石川 裕一, 勝見 章, 清井 仁, 齋藤 英彦, 國島 伸治, 小嶋 哲人, 松下 正
  • Organizer: 第81回日本血液学会学術集会
• [Book] 老年医療グリーンノート（悪性リンパ腫） (2021)
  • Author(s): 鴨下園子、勝見 章
  • Total Pages: 500
  • Publisher: 中外医学社
• [Book] 老年医療グリーンノート（骨髄異形成症候群） (2021)
  • Author(s): 勝見 章
  • Total Pages: 500
  • Publisher: 中外医学社