Identification of new skin disease biomarkers by lipid metabolome analyses and establishment of foundation for medical treatment

• Project/Area Number: 26461671
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: The University of Tokushima (2015-2016); Tokyo Metropolitan Institute of Medical Science (2014)
• Principal Investigator: Yamamoto Kei 徳島大学, 大学院生物資源産業学研究部, 准教授 (30304504)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プラズマローゲン / ホスホリパーゼA2 / 乾癬 / 接触性皮膚炎 / 皮膚癌 / リピドミクス / リゾホスファチジルエタノールアミン / ω３脂肪酸代謝産物 / 脂質 / 毛包 / 脂質メタボローム解析 / ホスホリパーゼＡ２ / 脂質代謝 / 質量分析 / モデルマウス

Outline of Final Research Achievements

This project aimed to create novel biomarkers by use of extensive lipid metabolome analyses of various skin diseases. As a result, epidermis-specifically expressed group IIF secretory phospholipase A2 was distributed in the uppermost regions of epidermal-hyperplasic diseases such as psoriasis, contact dermatitis and skin carcinogenesis. Ethanolamine lysoplasmalogen, a sPLA2-IIF-derived marker product, induced hyperproliferation and activation of keratinocytes and was novel lipid mediator for exacerbation of psoriasis and skin cancer. We found that group IIE sPLA2 was expressed abundantly in hair follicles and contributed to hair follicle formation. Furthermore, we found that dendritic sPLA2-IID improves inflammatory pathologies of contact dermatitis and psoriasis, while suppressing anti-tumor immunity to promote skin cancer by mobilizing omega-3 polyunsaturated fatty acid metabolites.

Research Products

• [Int'l Joint Research] University of Washington(米国)
• [Int'l Joint Research] CNRS(フランス)
• [Int'l Joint Research] CNRS(フランス)
• [Int'l Joint Research] University of Washington(米国)
• [Journal Article] Secreted Phospholipase A2 Specificity on Natural Membrane Phospholipids (2017)
  • Author(s): Yamamoto K, Miki Y, Sato H, Murase R, Taketomi Y, Murakami M
  • Journal Title: Methods Enzymol Volume: 583 Pages: 101-117
  • DOI: 10.1016/bs.mie.2016.09.007
  • Peer Reviewed / Open Access
• [Journal Article] Phosphatidylethanolamine dynamics are required for osteoclast fusion. (2017)
  • Author(s): Irie, A., Yamamoto, K., Miki, Y., and Murakami, M.
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 46715-46715
  • DOI: 10.1038/srep46715
  • NAID: 120006534988
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The new lipid mediators that modulate skin homeostasis and diseases (2016)
  • Author(s): 山本 圭
  • Journal Title: 生化学 Volume: 88 Issue: 6 Pages: 786-790
  • DOI: 10.14952/SEIKAGAKU.2016.880786
  • NAID: 40021054422
  • ISSN: 0037-1017
  • Year and Date: 2016-12-25
  • Peer Reviewed
• [Journal Article] Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility. (2016)
  • Author(s): Murase R, Sato H, Yamamoto K, Ushida A, Nishito Y, Ikeda K, Kobayashi T, Yamamoto T, Taketomi Y, Murakami M.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 13 Pages: 6895-6911
  • DOI: 10.1074/jbc.m116.715672
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer (2016)
  • Author(s): Miki Y, Kidoguchi Y, Sato M, Taketomi Y, Taya C, Muramatsu K, Gelb MH, Yamamoto K, Murakami M
  • Journal Title: J Biol Chem Volume: 291(30) Issue: 30 Pages: 15588-601
  • DOI: 10.1074/jbc.m116.734624
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression and Function of Group IIE Phospholipase A2 in Mouse Skin (2016)
  • Author(s): Yamamoto K, Miki Y, Sato H, Nishito Y, Gelb MH, Taketomi Y, Murakami M
  • Journal Title: J Biol Chem Volume: 291(30) Issue: 30 Pages: 15602-13
  • DOI: 10.1074/jbc.m116.734657
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of the Secreted Phospholipase A2 Gene Family in Immunology (2016)
  • Author(s): Murakami M, Yamamoto K, Miki Y, Murase R, Sato H, Taketomi Y
  • Journal Title: Adv Immunol Volume: 132 Pages: 91-134
  • DOI: 10.1016/bs.ai.2016.05.001
  • ISBN: 9780128047972
  • Peer Reviewed / Open Access
• [Journal Article] The role of group IIF secreted phospholipase A2 in epidermal homeostasis and hyperplasia. (2015)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., Taketomi, Y., Nishito, Y., Taya, C., Muramatsu, K., Ikeda, K., Nakanishi, H., Taguchi, R., Kambe, N., Kabashima, K., Lambeau, G., Gelb, M.H., and Murakami, M
  • Journal Title: J. Exp. Med. Volume: 212 Issue: 11 Pages: 1901-1919
  • DOI: 10.1084/jem.20141904
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Critical role of Phospholipase A2 group IID in age-related susceptibility to Severe Acute Respiratory Syndrome-CoV infection. (2015)
  • Author(s): Vijay, R., Hua, X., Meyerholz, D.K., Miki, Y., Yamamoto, K., Gelb, M.H., Murakami, M., and Perlman, S.
  • Journal Title: J. Exp. Med. Volume: 212 Issue: 11 Pages: 1851-1868
  • DOI: 10.1084/jem.20150632
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. (2014)
  • Author(s): Sato H, Taketomi Y, Ushida A, Isogai Y, Kojima T, Hirabayashi T, Miki Y, Yamamoto K, Nishito Y, Kobayashi T, Ikeda K, Taguchi R, Hara S, Ida S, Miyamoto Y, Watanabe M, Baba H, Miyata K, Oike Y, Gelb MH, Murakami M.
  • Journal Title: Cell Metab. Volume: 20 Issue: 1 Pages: 119-132
  • DOI: 10.1016/j.cmet.2014.05.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Emerging roles of secreted phospholipase A2 enzymes: the 3rd edition. (2014)
  • Author(s): Murakami M, Taketomi Y, Miki Y, Sato H, Yamamoto K, Lambeau G.
  • Journal Title: Biochimie Volume: 107Pt A Pages: 105-113
  • DOI: 10.1016/j.biochi.2014.09.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] A unique plasmalogen pathway driven by secreted phospholipase A2 regulates skin homeostasis and disease. (2016)
  • Author(s): Murakami, M. and Yamamoto, K.
  • Organizer: The 1st International Plasmalogen Symposium.
  • Place of Presentation: 九州大学医学部百年講堂（福岡県福岡市）
  • Year and Date: 2016-11-07
  • Int'l Joint Research
• [Presentation] Plasmalogen-lysophosphatidylethanolamine is a novel regulator and biomarker for epidermal-hyperplastic diseases. (2016)
  • Author(s): Yamamoto, K., Miki, Y., Taketomi, Y., and M. Murakami.
  • Organizer: The 1st International Plasmalogen Symposium.
  • Place of Presentation: 九州大学医学部百年講堂（福岡県福岡市）
  • Year and Date: 2016-11-07
  • Int'l Joint Research
• [Presentation] IID型分泌性ホスホリパーゼA２は抗腫瘍免疫を抑制する (2016)
  • Author(s): 城戸口優、山本圭、三木寿美、村上誠
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] IID型分泌性ホスホリパーゼA２は皮膚免疫疾患を普遍的に抑制する (2016)
  • Author(s): 三木寿美、城戸口優、山本圭、村上誠
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 炎症および癌病態におけるIID型sPLA２の二面的役割 (2016)
  • Author(s): 三木寿美、城戸口優、山本圭、村上誠
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: にぎわい交遊館ＡＵ（秋田県秋田市）
  • Year and Date: 2016-06-09
• [Presentation] 皮膚の恒常性と病態における二種のsPLA２の発現と機能 (2016)
  • Author(s): 山本圭、三木寿美、佐藤弘泰、武富芳隆、村上誠
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: にぎわい交遊館ＡＵ（秋田県秋田市）
  • Year and Date: 2016-06-09
• [Presentation] マスト細胞を制御する第二のAnaphylactic sPLA２の同定 (2016)
  • Author(s): 武富芳隆、砂川アンナ、入江敦、山本圭、三木寿美、佐藤弘泰、小林哲幸、村上誠
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: にぎわい交遊館ＡＵ（秋田県秋田市）
  • Year and Date: 2016-06-09
• [Presentation] 表皮肥厚性疾患を調節する新しい生理活性脂質の発見 (2016)
  • Author(s): 山本圭、村上誠
  • Organizer: 第57回日本生化学会 中国・四国支部例会
  • Place of Presentation: 高知大学医学部（高知県南国市）
  • Year and Date: 2016-05-27
• [Presentation] The two secreted phospholipase A2s PLA2G2F and PLA2G2E play distinct roles in skin homeostasis and diseases. (2016)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., Taketomi, Y., Lambeau, G., Gelb, M., and Murakami, M.
  • Organizer: 7th International conference on phospholipase A2 and lipid mediators.
  • Place of Presentation: La Jolla, USA
  • Year and Date: 2016-05-19
  • Int'l Joint Research
• [Presentation] ウシ生乳由来リポカリン型プロスタグランジンD合成酵素の精製と酵素学的性質 (2016)
  • Author(s): 川井恵理佳、田中充樹、瀬来由衣、戸田圭祐、目賀拓斗、川上祐生、高橋吉孝、木本眞順美、山本圭、村上誠、山本登志子
  • Organizer: 第70回日本栄養・食糧学会大会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2016-05-13
• [Presentation] 表皮肥厚性疾患を調節する新しい脂質メカニズムの発見 (2016)
  • Author(s): 山本 圭
  • Organizer: 2015年度 第6回学際的脂質創生研究部会
  • Place of Presentation: 徳島大学工業会館（徳島県徳島市）
  • Year and Date: 2016-01-22
  • Invited
• [Presentation] 健康と病態に関わる脂質ネットワークの研究 (2016)
  • Author(s): 山本圭
  • Organizer: 第2回BRIGHTシンポジウム
  • Place of Presentation: 徳島大学薬学部講堂（徳島県徳島市）
  • Invited
• [Presentation] 癌病態におけるIID型分泌性ホスホリパーゼA2の役割 (2015)
  • Author(s): 城戸口 優, 山本 圭, 三木 寿美, 村上 誠
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Plasmalogen-lysophosphatidylethanolamine driven by group IIF sPLA2 underlies epidermal-hyperplastic disorders. (2015)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., Taketomi, Y., Kambe, N., Kabashima, K., Lambeau,G., Gelb, M.H., and Murakami, M.
  • Organizer: The 14th International Conference on Bioactive Lipids in Inflammation, Cancer and Related Diseases.
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] Group X sPLA2 mobilizes omega-3 polyunsaturated fatty acid metabolites to protect from colitis. (2015)
  • Author(s): Murase, R., Taketomi, Y., Sato, H., Yamamoto, K., Yamamoto, T. and Murakami, M.
  • Organizer: The 14th International Conference on Bioactive Lipids in Inflammation, Cancer and Related Diseases.
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] Skin abnormalities in group III secreted phospholipase A2-deficient mice. (2015)
  • Author(s): Taketomi, Y., Endo, Y., Yamamoto, K., Kobayashi, T. and Murakami, M.
  • Organizer: The 14th International Conference on Bioactive Lipids in Inflammation, Cancer and Related Diseases.
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] IIF型分泌性ホスホリパーゼA2により産生されるアルケニル型リゾホスファチジルエタノールアミンは表皮肥厚性疾患のバイオマーカーである (2015)
  • Author(s): 山本 圭, 三木 寿美, 村上 誠
  • Organizer: 第57回日本脂質生化学会
  • Place of Presentation: 一橋大学一橋講堂（東京都千代田区）
  • Year and Date: 2015-05-28
• [Presentation] A unique lipid pathway driven by group IIF sPLA2 undelies epidermal-hyperplasic disorders (2015)
  • Author(s): Yamamoto, K., Miki, Y., Taketomi, Y., Kambe, N., Kabashima, K., Lambeau, G., Gelb, M., Murakami, M.
  • Organizer: The 6th International Conference on Phospholipase A2 and Lipid Mediators (PLM2015)
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-02-10 – 2015-02-13
• [Presentation] Group IIF sPLA2 promotes skin carcinogenesis (2015)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., Murakami, M.
  • Organizer: The 6th International Conference on Phospholipase A2 and Lipid Mediators (PLM2015)
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-02-10 – 2015-02-13
• [Presentation] 新規リゾフォスファチジルエタノールアミンは表皮PLA2依存的な表皮肥厚性疾患のバイオマーカーである. (2014)
  • Author(s): 山本圭
  • Organizer: Conference for BioSignal and Medicine (CBSM) 2
  • Place of Presentation: ラフォーレ修善寺（静岡県伊豆市）
  • Year and Date: 2014-11-22 – 2014-11-23
  • Invited
• [Presentation] アルケニル型リゾホスファチジルエタノールアミンはIIF型分泌性ホスホリパーゼA2依存的な表皮肥厚疾患のバイオマーカーである． (2014)
  • Author(s): 山本圭、三木寿美、村上誠．
  • Organizer: 第87回日本生化学会.
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Secreted phospholipase PLA2G2F regulates epidermal homeostasis and hyperplasic disorders by mobilizing unique lipid products. (2014)
  • Author(s): Yamamoto, K., Miki, Y., Taketomi, Y., and Murakami, M.
  • Organizer: 2014 Yonsei-Igakuken Joint Symposium.
  • Place of Presentation: ソウル（大韓民国）
  • Year and Date: 2014-06-19 – 2014-06-22
• [Remarks] 皮膚の健康と病気を調節する脂質の新しい役割の発見
  • URL: http://www.igakuken.or.jp/topics/2015/1005.html
• [Remarks]
  • URL: http://www.igakuken.or.jp/lipid/