Identification of VWF-HBD in vascular growth and interaction with an inhibitory VEGF isoform
Project/Area Number |
20K08711
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | Nagoya University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
鈴木 伸明 名古屋大学, 医学部附属病院, 講師 (70637686)
菊地 良介 岐阜大学, 医学部附属病院, 臨床検査技師長 (30721435)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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Keywords | ECFC / VWF / VWD / Weibel-Palade body / DDAVP / Type 3 VWD / Platelet glycoprotein Ib / multimer / von Willebrand factor / von Willebrand disease / Type 3 / VEGF / angiogenesis / GRIb / Heparin / 血管新生 / von Willebrand facor / GPIb / heparin / vascular growth |
Outline of Research at the Start |
VWFは、そのヘパリン結合ドメインがGFに結合し、創傷治癒において血管新生を促進するという新しい機能が近年指摘されている。我々はVWFのヘパリン結合部位 (HBD)をin vitroでピンポイント同定しており、本研究ではこの結合部位のVWFの血管新生機能における重要性を検討、一部のVWD患者に見られる血管新生障害の原因としての「血管新生抑制型VEGF-Aアイソフォーム(VEGF-A165b)」の負の影響を検討することにより、血漿・内皮細胞由来のVWFがヘパリンへの結合を介して血管外マトリックスへ結合することにより、どのようにGFの血管新生を調節するか明らかにする。
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Outline of Final Research Achievements |
Type 3 VWD, the most severe form of von Willebrand disease (VWD), causes refractory bleeding that does not respond to replacement therapy. Angiodysplasia has been implicated in such bleeding, but the specific pathomechanism has not been elucidated. In this study, we focused on the angiogenic potential of ECMC derived from type 3 patients, and also examined the expression and intracellular profiles of mutant VWF in VWD type 3 patients with trace amount of VWF levels and a novel p.Gly2752Ser mutation. We analyzed the expression and intracellular dynamics of mutant VWF in patients with VWD type 3.
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Academic Significance and Societal Importance of the Research Achievements |
VWFは内皮細胞という再現の難しい培養細胞種から分泌され、またWPBという特徴的な小胞体に貯留され、刺激にて分泌されるという特徴を有する。ECFCは、血管内皮細胞環境を患者由来として直接構築できる特徴がある。本研究では従来のTransfectionによる発現検討と組み合わせ、優性遺伝形式を取るVWDにおけるDominant-negative effectの細胞学的な機構を詳細に検討を行うことができた。一方、正常アレル由来の発現を最適化すれば、VWF濃縮製剤を使用することなく治療が可能となるはずである。本研究で得られた最適な分泌刺激方法により新たなVWD治療の基盤モデルとなることが期待される。
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Report
(4 results)
Research Products
(65 results)
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[Journal Article] VWF-Gly2752Ser, a novel non-cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C-terminal dimer formation2022
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.
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Journal Title
J Thromb Haemost
Volume: 20
Issue: 8
Pages: 1784-1796
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
J Thromb Haemost.
Volume: -
Issue: 4
Pages: 920-930
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Guidelines for the Management of von Willebrand Disease 20212021
Author(s)
日笠 聡, 渥美 達也, 石黒 精, 金子 誠, 高橋 芳右, 野上 恵嗣, 藤井 輝久, 堀内 久徳, 松井 太衛, 毛利 博, 森下 英理子, 松下 正, 朝比奈 俊彦, 天野 景裕, 上田 恭典, 岡本 好司, 小亀 浩市, 佐道 俊幸, 瀧 正志, 長尾 梓, 西尾 健治, 西田 恭治, 西野 正人, 藤村 吉博, 松本 雅則, 宮川 義隆, 八木 秀男, 和田 英夫
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Journal Title
Japanese Journal of Thrombosis and Hemostasis
Volume: 32
Issue: 4
Pages: 413-481
DOI
NAID
ISSN
0915-7441, 1880-8808
Related Report
Peer Reviewed
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[Journal Article] Myh9 R702C is associated with erythroid abnormality with splenomegaly in mice2021
Author(s)
Kanematsu T, Suzuki N, Tamura S, Suzuki A, Ishikawa Y, Katsumi A, Kiyoi H, Saito H, Kunishima S, Kojima T, Matsushita T.
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Journal Title
Nagoya Journal of Medical Science
Volume: 83
Issue: 1
Pages: 75-86
DOI
NAID
ISSN
0027-7622
URL
Related Report
Peer Reviewed / Open Access
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[Journal Article] Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation.2021
Author(s)
Goto T, Murata M, Nishida T, Terakura S, Kamoshita S, Ishikawa Y, Ushijima Y, Adachi Y, Suzuki S, Kato K, Hirakawa A, Nishiwaki S, Nishio N, Takahashi Y, Kodera Y, Matsushita T, Kiyoi H.
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Journal Title
Stem Cells Transl Med.
Volume: 10(4)
Issue: 4
Pages: 542-553
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Safety and efficacy of percutaneous radiofrequency ablation for hepatocellular carcinoma patients with haemophilia.2021
Author(s)
Yamamoto T, Imai N, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Fujishiro M.
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Journal Title
Haemophilia.
Volume: 27(1)
Issue: 1
Pages: 100-107
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Japanese multi-institutional collaborative study of antigen-positive red blood cell (RBC) transfusions in patients with corresponding RBC antibodies.2020
Author(s)
Yamada C, Takeshita A, Ohto H, Ishimaru K, Kawabata K, Nomaguchi Y, Haraguchi Y, Abe M, Sobue K, Takenouchi H, Takadate J, Kamimura M, Katai A, Kasai D, Minami Y, Sugimoto T, Michino J, Nagai K, Kumagai M, Hasegawa Y, Ishizuka K, Ohtomo N, Yamada N, Muroi K, Matsushita T, Takahashi K.
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Journal Title
Vox Sang.
Volume: -
Issue: 5
Pages: 456-465
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Higher FVIII:C Measured by Chromogenic Substrate Assay Than by One-Stage Assay Is Associated With Silent Hemophilic Arthropathy2020
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
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Journal Title
Thromb Res
Volume: 188
Pages: 103-105
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Presentation] p.G2752S Severely Affects Dimerization of von Willebrand Factor: An Analysis of Type 3 von Willebrand Disease2021
Author(s)
S. Okamoto, S. Tamura, N. Suzuki, K. Odaira, Y. Hayakawa, A. Suzuki, T. Kanematsu, F. Hayakawa, H. Kiyoi, T. Kojima, T. Matsushita
Organizer
ISTH 2021
Related Report
Int'l Joint Research
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[Presentation] A Critical Role of Carboxyl-Terminal Alpha-Helix in the Secretion of Coagulation Factor XI2021
Author(s)
Y. Hayakawa, S. Tamura, N. Suzuki, K. Odaira, M. Tokoro, F. Kawashima, F. Hayakawa, A. Takagi, A. Suzuki, S. Okamoto, T. Kanemats3, T. Matsushita, T. Kojima
Organizer
ISTH 2021
Related Report
Int'l Joint Research
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[Presentation] The Haemophilia A Patients whose FVIII: C by Chromogenic Substrate Assay were Higher than by One-Stage Substrate Assay Showed Risk of Development of Haemophiliac Arthropathy Silently2021
Author(s)
N. Suzuki, N. Takahashi, A. Suzuk2, S. Tamura, S. Suzuki, Y. Hattori, M. Kakihara, M. Ogawa, T. Kanematsu, T. Kojima, T. Kojima, H. Kiyoi, N. Ishiguro, T. Matsushita
Organizer
ISTH 2021
Related Report
Int'l Joint Research
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[Presentation] Investigation of a Significant Factor to Improve an Establishment of Endothelial Colony Forming Cell2021
Author(s)
S. Okamoto, N. Suzuki, T. Kanematsu, A. Suzuki, K. Odaira, M. Tokoro, Y. Hayakawa, S. Tamura, F. Hayakaw5, H. Kiyoi, T. Kojima, T. Matsushita
Organizer
ISTH 2021
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Int'l Joint Research
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[Presentation] 1009 The E6cacy and Safety of Caplacizumab in Japanese Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): An Open-Label, Phase 2/3 Study2021
Author(s)
Yoshitaka Miyakawa , Kazunori Imada, Satoshi Ichikawa, Hitoji Uchiyama, Yasunori Ueda, Akihito Yonezawa, Shigeki Fujitani, Hiroshi Handa, Tadashi Matsushita, Hidesaku Asakura, Kenji Nishio, Kodai Suzuki, Yasuhiro Hashimoto , Shinobu Ohshima , Sayaka Tahara , Tomoyuki Tanaka, and Masanori Matsumoto,
Organizer
ASH2021
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[Presentation] Endothelial colony forming cells(ECFCs)樹立法の標準化への試み2020
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岡本 修一, 鈴木 伸明, 兼松 毅, 鈴木 敦夫, 大平 晃也, 所 真昼, 早川 友梨, 田村 彰吾, 早川 文彦, 清井 仁, 小嶋 哲人, 松下 正
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第42回日本血栓止血学会学術集会
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[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
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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
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[Presentation] 特発性血栓症患者のゲノム情報を用いた層別化による病態解明研究2020
Author(s)
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[Presentation] C末端伸長変異型Factor XIにおける分泌異常の解析2020
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