Development of a mouse model of microscopic polyangiitis

• Project/Area Number: 15K14947
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Akita University
• Principal Investigator: Sasaki Takehiko 秋田大学, 医学(系)研究科(研究院), 教授 (50333365)
• Co-Investigator(Kenkyū-buntansha): 木村 洋貴 秋田大学, 学内共同利用施設等, 特任助教 (30382899)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 血管炎 / リン脂質 / 好中球 / 顕微鏡的多発血管炎 / 病態モデル

Outline of Final Research Achievements

Microscopic polyangiitis (MPA) is a form of small vessel vasculitis (SVV) primarily affecting arterioles, capillaries and venules. Aberrant neutrophil extracellular traps (NETs) play a role in MPA induction but a lack of suitable mouse models has precluded elucidation of the mechanism. We have developed a new mouse model of MPA based on administration of a novel fungal immunostimulant, termed CANDE. CANDE induced NET formation both in vitro and in vivo. CANDE-treated mice displayed disease closely recapitulating human MPA, with anti-neutrophil cytoplasmic autoantibodies (ANCAs) in serum; necrotizing SVV in the lung; and necrotizing glomerulonephritis with crescent formation. Using this MPA model, we demonstrate that loss of phosphoinositide-3-kinase p110g; inhibits NET formation in vitro and in vivo, decreases serum ANCA levels, and alleviates organ damage.

Research Products

• [Int'l Joint Research] Univ. of Harvard Medical School(米国)
• [Int'l Joint Research] University College London(英国)
• [Int'l Joint Research] Univ. of Toronto(Canada)
• [Int'l Joint Research] Univ. of Monash(Australia)
• [Int'l Joint Research] IMBA(Austria)
• [Int'l Joint Research]
• [Journal Article] Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy. (2017)
  • Author(s): Kimura H, Eguchi S, Sasaki J, Kuba K, Nakanishi H, Takasuga S, Yamazaki M, Goto A, Watanabe H, Itoh H, Imai Y, Suzuki A, Mizushima N, Sasaki T
  • Journal Title: JCI Insight Volume: 2 Issue: 1 Pages: 89462-89478
  • DOI: 10.1172/jci.insight.89462
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Decreased 16:0/20:4-phosphatidylinositol level in the post-mortem prefrontal cortex of elderly patients with schizophrenia. (2017)
  • Author(s): Matsumoto J, Nakanishi H, Kunii Y, Sugiura Y, Yuki D, Wada A, Hino M, Niwa SI, Kondo T, Waki M, Hayasaka T, Masaki N, Akatsu H, Hashizume Y, Yamamoto S, Sato S, Sasaki T, Setou M, Yabe H.
  • Journal Title: Sci Rep. Volume: 7 Issue: 7 Pages: 45050-45050
  • DOI: 10.1038/srep45050
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Myeloid cell-specific inositol polyphosphate-4-phosphatase type I knockout mice impair bacteria clearance in a murine peritonitis model. (2016)
  • Author(s): Morioka S, Nigorikawa K, Sasaki J, Hazeki K, Kasuu Y, Sasaki T, Hazeki O
  • Journal Title: Innate Immun Volume: 6 Issue: 6 Pages: 444-444
  • DOI: 10.1177/1753425916652714
  • Peer Reviewed / Open Access
• [Journal Article] イノシトールリン脂質のがん転移への関与 : "invadopodia"の形成機構 (2016)
  • Author(s): 坂東 倫行、佐々木 雄彦
  • Journal Title: 医学のあゆみ Volume: 257 Pages: 1211-1215
• [Journal Article] Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment. (2015)
  • Author(s): Ip, LR., Poulogiannis, G., Viciano, FC., Sasaki, J., Kofuji, S., Spanswick, VJ., Hochhauser, D., Hartley, JA., Sasaki, T., Gewinner, CA.
  • Journal Title: Oncotarget Volume: 6 Pages: 10548-10562
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] INPP4B is a PtdIns(3,4,5)P3 phosphatase that can act as a tumor suppressor. (2015)
  • Author(s): Kofuji S, Kimura H, Nakanishi H, Nanjo H, Takasuga S, Liu H, Eguchi S, Nakamura R, Itoh R, Ueno N, Asanuma K, Huang M, Koizumi A, Habuchi T, Yamazaki M, Suzuki A, Sasaki J, Sasaki T
  • Journal Title: Cancer Discovery Volume: in press Issue: 7 Pages: 730-9
  • DOI: 10.1158/2159-8290.cd-14-1329
  • Peer Reviewed / Open Access
• [Journal Article] In vivo role of INPP4B in tumor and metastasis suppression through regulation of PI3K/AKT signaling at endosomes. (2015)
  • Author(s): Chew CL, Lunardi A, Gulluni F, Ruan DT, Chen M, Salmena L, Nishino M, Papa A, Ng C, Fung J, Clohessy JG, Sasaki J, Sasaki T, Bronson RT, Hirsch E, Pandolfi PP
  • Journal Title: Cancer Discovery Volume: in press Issue: 7 Pages: 740-751
  • DOI: 10.1158/2159-8290.cd-14-1347
  • Peer Reviewed
• [Journal Article] Inositol Polyphosphate-4-Phosphatase Type I Negatively (2015)
  • Author(s): Nigorikawa, K., Hazeki, K., Sasaki, J., Omori, Y., Miyake, M., Morioka, S., Guo, Y., Sasaki, T., Hazeki, O
  • Journal Title: PLoS One Volume: 10 Issue: 11 Pages: 740-751
  • DOI: 10.1371/journal.pone.0142091
  • Peer Reviewed / Open Access
• [Journal Article] The ML1Nx2 Phosphatidylinositol 3,5-Bisphosphate Probe Shows Poor Selectivity in Cells. (2015)
  • Author(s): Hammond GR, Takasuga S, Sasaki T, Balla T.
  • Journal Title: PLoS One Volume: 10 Issue: 10 Pages: e0139957-e0139957
  • DOI: 10.1371/journal.pone.0139957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Localizing the lipid products of PI3Kγ in neutrophils (2015)
  • Author(s): Norton L, Lindsay Y, Deladeriere A, Chessa T, Guillou H, Suire S, Lucocq J, Walker S, Andrews S, Segonds-Pichon A, Rausch O, Finan P, Sasaki T, Du CJ, Bretschneider T, Ferguson GJ, Hawkins PT, Stephens L.
  • Journal Title: Adv Biol Regul Volume: 60 Pages: 36-45
  • DOI: 10.1016/j.jbior.2015.10.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dysregulated YAP1/TAZ and TGF signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice (2015)
  • Author(s): Nishio, M., Sugimachi, K., Goto, H., Wang, J., Morikawa, T., Miyachi, Y., Takano, Y., Hikasa, H., Itoh, T., Suzuki, S.O., Kurihara, H., Aishima, S., Leask, A., Sasaki, T., Nakano, T., Nishina, H., Nishikawa, Y., Sekido, Y., Nakao, K., Shin-ya, K., Mimori, K. and Suzuki, A.
  • Journal Title: PNAS Volume: 113 Issue: 1 Pages: 71-80
  • DOI: 10.1073/pnas.1517188113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] INPP4BはPTEN欠損による発がんへのフェイルセーフ機構を担う (2015)
  • Author(s): 小藤智史，佐々木雄彦
  • Journal Title: 実験医学 Volume: 34 Pages: 450-453
• [Presentation] リピドミクスによる疾患研究 (2016)
  • Author(s): 佐々木雄彦
  • Organizer: 神戸大学医学部セミナー
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2016-12-22
  • Invited
• [Presentation] A method for studying quality of phosphoinositides (2016)
  • Author(s): Takehiko Sasaki, Hiroki Nakanishi, Satoshi Eguchi, Masaki Ishikawa, Akira Suzuki, Junko Sasaki
  • Organizer: 第３９回日本分子生物学会年会（MBSJ2016）
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] イノシトールリン脂質代謝と病態 (2016)
  • Author(s): 佐々木雄彦
  • Organizer: 脂質栄養学会第２５回大会
  • Place of Presentation: 秋田県秋田市
  • Year and Date: 2016-09-17
  • Invited
• [Presentation] ホスホイノシタイドによる生体調節機構 (2016)
  • Author(s): 佐々木雄彦
  • Organizer: 第28回高遠・分子細胞生物学シンポジウム
  • Place of Presentation: 長野県伊那市
  • Year and Date: 2016-08-26
  • Invited
• [Presentation] ω3系脂肪酸代謝産物による肝庇護作用 (2016)
  • Author(s): 森井真也子、上野紀子、中西広樹、蛇口琢、渡部亮、吉野裕顕、佐々木雄彦
  • Organizer: 第15回生命科学研究会
  • Place of Presentation: 東京都港区
  • Year and Date: 2016-06-17
• [Presentation] Measuring Phosphoinositides at Molecular Species Level (2015)
  • Author(s): Hiroki Nakanishi, Satoshi Eguchi, Masaki Ishikawa, Akira Suzuki, Junko Sasaki, Takehiko Sasaki
  • Organizer: 第38回日本分子生物学会年会・第88回生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] 心肥大におけるホスホイノシタイド代謝酵素Vps34のタンパク質分解機構の役割 (2015)
  • Author(s): 木村洋貴、江口賢史、久場敬司、今井由美子、高須賀俊輔、伊藤玲悦、中村亮太郎、中西広樹、石川将己、佐々木純子、山崎正和、佐々木雄彦
  • Organizer: 第38回日本分子生物学会年会・第88回生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
  • Invited
• [Presentation] イノシトールリン脂質研究の新しい方法論の提示 (2015)
  • Author(s): 中西広樹、小藤智史、江口賢史、中村亮太郎、石川将己、高須賀俊輔、佐々木純子、佐々木雄彦
  • Organizer: 第14回生命科学研究会
  • Place of Presentation: 神奈川
  • Year and Date: 2015-06-27
  • Invited
• [Book] 脂質代謝異常と関連疾患（下巻） (2015)
  • Author(s): 佐々木雄彦
  • Total Pages: 413
  • Publisher: エル・アイ・シー社
• [Remarks] 研究室HP
  • URL: http://www.med.akita-u.ac.jp/~bisei/
• [Remarks] 研究室ＨＰ
  • URL: http://www.med.akita-u.ac.jp/~bisei/
• [Patent(Industrial Property Rights)] 新規リン脂質およびその利用 (2017)
  • Inventor(s): 佐々木雄彦、中西広樹、石川将己、上野紀子、江口賢史、佐々木純子
  • Industrial Property Rights Holder: 秋田大学、Akita Lipid Technologies
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-051354
  • Filing Date: 2017-03-14
• [Patent(Industrial Property Rights)] ホスホイノシタイド分離測定法の開発 (2016)
  • Inventor(s): 中西広樹、佐々木雄彦、佐々木純子、江口賢史、中西貴代
  • Industrial Property Rights Holder: 秋田大学、Akita Lipid Technologies
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-144177
  • Filing Date: 2016-07-20