Metabolism and functions of novel phospholipids

• Project/Area Number: 26253006
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• 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): 中西 広樹 秋田大学, 学内共同利用施設等, 助教 (10466740) ; 江口 賢史 秋田大学, 医学(系)研究科(研究院), 助教 (70457117) ; 高須賀 俊輔 秋田大学, 医学(系)研究科(研究院), 助教 (90375262)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥40,820,000 (Direct Cost: ¥31,400,000、Indirect Cost: ¥9,420,000); Fiscal Year 2016: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2015: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2014: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
• Keywords: 脂質 / 細胞膜 / シグナル伝達 / リン脂質 / 病態モデル / がん / 疾患モデル / 病態モデルマウス

Outline of Final Research Achievements

Genetic and environmental triggers of diseases often alter bioactive lipid products in cellular membranes. For example, membrane phospholipids modulate important biological processes such as cell cycle, survival, metabolism and motility, which are often disrupted in cancer. The central focus of our research is to understand disease-associated signaling networks which involve membrane phospholipids. The strength of our research relies on mass spectrometry technologies for lipidomics as well as genetically modified mouse disease models. We have identified novel phospholipids, the levels of which are increased in various pathological conditions associated with cancers and inflammatory diseases in mice. Our genetic and biochemical studies revealed that one of these novel lipids can be liberated from the membrane and acts as an extracellular signaling molecule, and identified the enzymes involved in its metabolism.

Research Products

• [Int'l Joint Research] UC Irvine/Cornell Univ/Harvard Medical School(米国)
• [Int'l Joint Research] University College London/Babraham Inst(英国)
• [Int'l Joint Research] IMBA(Austria)
• [Int'l Joint Research] Harvard/Cornell/Pittsburgh(米国)
• [Int'l Joint Research] University College London/Cambridge/Babraham Inst(英国)
• [Int'l Joint Research] IMBA(Ａｕｓｔｒｉａ)
• [Int'l Joint Research] Università degli Studi di Torino(Ｉｔａｌｙ)
• [Int'l Joint Research] Université Libre de Bruxelles(Belgium)
• [Int'l Joint Research]
• [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] 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] 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] 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
• [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] 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: in press
  • Peer Reviewed
• [Journal Article] Dachsous-Dependent Asymmetric Localization of Spiny-Legs Determines Planar Cell Polarity Orientation in Drosophila. (2014)
  • Author(s): Ayukawa T., Akiyama M., Mummery-Widmer JL., Stoeger T., Sasaki J., Knoblich JA., Senoo H., Sasaki T., Yamazaki M.
  • Journal Title: Cell Rep. Volume: 8 Issue: 2 Pages: 610-621
  • DOI: 10.1016/j.celrep.2014.06.009
  • Peer Reviewed / Open Access
• [Presentation] リピドミクスによる疾患研究 (2016)
  • Author(s): 佐々木雄彦
  • Organizer: 九州大学大学院歯学府セミナー
  • Place of Presentation: 福岡県・福岡市
  • Year and Date: 2016-12-21
  • Invited
• [Presentation] A method for studying quality of phosphoinositides (2016)
  • Author(s): Takehiko 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
• [Presentation] A New Methodology for Studying Phosphoinositide Signaling at the Molecular Species Level. (2015)
  • Author(s): Takehiko Sasaki
  • Organizer: Keystone Symposium “PI 3-Kinase Signaling Pathways in Disease”
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-01-15
  • Invited
• [Presentation] Critical roles of class III PI3K in myofibril maintenance and protein quality control in cardiomyocytes (2014)
  • Author(s): Takehiko Sasaki
  • Organizer: Symposium on Hormones and Cell Regulation European Society of Endocrinology
  • Place of Presentation: Mont Ste Odile, France
  • Year and Date: 2014-10-09
  • Invited
• [Book] 脂質代謝異常と関連疾患（上巻） (2015)
  • Author(s): 佐々木雄彦（編集）
  • Total Pages: 413
  • Publisher: （株）エル・アイ・シー
• [Book] 脂質代謝異常と関連疾患（下巻） (2015)
  • Author(s): 佐々木雄彦（編集）
  • Total Pages: 477
  • Publisher: （株）エル・アイ・シー
• [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): 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: 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): 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: 2016-144177
  • Filing Date: 2016-07-20