Establishment of autoimmune disease therapies based on the elucidation of target genes

• Project/Area Number: 20679005
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: The University of Tokushima
• Principal Investigator: YASUTOMO Koji 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (30333511)
• Project Period (FY): 2008 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥105,560,000 (Direct Cost: ¥81,200,000、Indirect Cost: ¥24,360,000); Fiscal Year 2012: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2011: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2010: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2009: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥32,760,000 (Direct Cost: ¥25,200,000、Indirect Cost: ¥7,560,000)
• Keywords: 自己免疫疾患 / T細胞 / ゲノム解析 / Notch / 自己免疫 / Tリンパ球 / 転写調節 / 細胞治療 / 分子標的治療

Research Abstract

We aim to reveal the molecular mechanisms to maintain immune homeostasis in order to establish therapeutic strategies for human immune-mediated disorders. We demonstrated the crucial roles of Notch signaling in cytotoxic T cellsresponses, IL-22 production from CD4+ T cells, the differentiation of macrophages in the small intestine and maintenance of memory T cells. Furthermore, we identified PSMB8 as a causative gene for a new type of autoinflammatory syndrome.

Assessment Rating

Verification Result (Rating)

B

Research Products

• [Journal Article] The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+cells (2013)
  • Author(s): Nakajima K, Maekawa Y, KataokaK, IshifuneC, NishidaJ, ArimochiH, KitamuraA, YoshimotoT, TomitaS, NagahiroS, Yasutomo K
  • Journal Title: Nature Communications
  • Peer Reviewed
• [Journal Article] Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice (2012)
  • Author(s): ian G, Arimochi H, Kitamura A, Nishida J, Li S, Kishihara K, Maekawa Y, Yasutomo K
  • Journal Title: J Immunol Volume: 188 Issue: 5 Pages: 2227-34
  • DOI: 10.4049/jimmunol.1102586
  • Peer Reviewed
• [Journal Article] Notch2 regulates the development of marginal zone B cells through Fos (2012)
  • Author(s): Iwahashi S, Maekawa Y, Nishida J, Ishifune C, Kitamura A, Arimochi H, Kataoko K, Chiba S, Shimada M, Yasutomo K
  • Journal Title: iochem Biophys Res Commun Volume: 418 Issue: 4 Pages: 701-707
  • DOI: 10.1016/j.bbrc.2012.01.082
  • Peer Reviewed
• [Journal Article] Dll4-Fc, an inhibitor of Dll4-Notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-kappa-B activity. (2012)
  • Author(s): Kuramoto T, Goto H, Mitsuhashi A, Tabata S, Ogawa H, Uehara H, Sijo A, Kakiuchi S, Maekawa, Yasutomo K, Hanibuchi M, Akiyama SI, Sone S, Nishioka Y
  • Journal Title: Mol Cancer Ther Volume: 11 Issue: 12 Pages: 2578-2587
  • DOI: 10.1158/1535-7163.mct-12-0640
  • Peer Reviewed
• [Journal Article] Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice (2012)
  • Author(s): Gojin Lian
  • Journal Title: J Immunol Volume: 188 Pages: 2227-2234
  • Peer Reviewed
• [Journal Article] Notch2 regulates the development of marginal zone B cells through Fos (2012)
  • Author(s): Shuichi Iwahashi
  • Journal Title: Biochem Biophys Res Commun Volume: 418 Pages: 701-707
  • Peer Reviewed
• [Journal Article] A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans (2011)
  • Author(s): Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, Toyoshima Y, Takahashi H, Standley DM, Tanaka K, Hamazaki J, Murata S, Obara K, Toyoshima I, Yasutomo K.
  • Journal Title: J Clin Invest Volume: 121 Issue: 10 Pages: 4150-4160
  • DOI: 10.1172/jci58414
  • Peer Reviewed
• [Journal Article] Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (2011)
  • Author(s): M.Xu
  • Journal Title: Eur J Immunol Volume: 41 Issue: 10 Pages: 2828-2839
  • DOI: 10.1002/eji.201141291
  • Peer Reviewed
• [Journal Article] Low-dose lipopolysaccharide affects lung allergic responses by regulating Jagged1 expression on antigen-pulsed dendritic Cells. (2011)
  • Author(s): Okamoto M, Takeda K, Lucas JJ, Joetham A, Yasutomo K, Gelfand EW
  • Journal Title: Int Arch Allergy Immunol Volume: 157 Issue: 1 Pages: 65-72
  • DOI: 10.1159/000324836
  • Peer Reviewed
• [Journal Article] Notch signaling regulates the development of a novel type of Thy1-expressing dendritic cell in the thymus (2011)
  • Author(s): Ishifune C, et al
  • Journal Title: Eur J Immunol Volume: 41 Issue: 5 Pages: 1309-20
  • DOI: 10.1002/eji.201041159
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine (2011)
  • Author(s): Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito T, Maruyama H, Morishita Y, Nakagami-Yamaguchi E, Kumano K, Yagita H, Fukayama M, Ogawa S, Kurokawa M, Yasutomo K, Chiba S
  • Journal Title: Blood Volume: 117 Issue: 1 Pages: 128-134
  • DOI: 10.1182/blood-2010-07-289611
  • NAID: 120007137632
  • Peer Reviewed
• [Journal Article] Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. (2010)
  • Author(s): Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K, Yasutomo K
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Issue: 13 Pages: 5943-5948
  • DOI: 10.1073/pnas.0911755107
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for potent anti-tumor immunity in vivo (2010)
  • Author(s): Sugimoto K, Maekawa Y, Kitamura A, Nishida J, Koyanagi A, Yagita H, Kojima H, Chiba S, Shimada M, Yasutomo K
  • Journal Title: J Immunol Volume: 184 Issue: 9 Pages: 4673-4678
  • DOI: 10.4049/jimmunol.0903661
  • Peer Reviewed
• [Journal Article] Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese (2010)
  • Author(s): Nishimoto K, Kochi Y, Ikari K, Yamamoto K, Suzuki A, Shimane K, Nakamura Y, Yano K, Iikuni N, Tsukahara S, Kamatani N, Okamoto H, Kaneko H, Kawaguchi Y, Hara M, Toyama Y, Horiuchi T, Tao K, Yasutomo K, Hamada D, Yasui N, Inoue H, Itakura M, Yamanaka H, Mo
  • Journal Title: Ann Rheum Dis Volume: 69 Issue: 2 Pages: 368-373
  • DOI: 10.1136/ard.2008.104315
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for potent anti-tumor immunity in vivo (2010)
  • Author(s): Koji Sugimoto, et al.
  • Journal Title: The Journal of Immunology Volume: 184 Pages: 4673-4678
  • Peer Reviewed
• [Journal Article] Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor (2010)
  • Author(s): Muhammad Alam, et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 5943-5948
  • Peer Reviewed
• [Journal Article] Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese. (2010)
  • Author(s): Kazumasa Nishimoto
  • Journal Title: Annals of the Rheumatic diseases 69 Pages: 368-373
  • Peer Reviewed
• [Journal Article] Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. (2010)
  • Author(s): Alam Muhammad
  • Journal Title: Proc Natl Acad Sci USA 107 Pages: 5943-5948
  • Peer Reviewed
• [Journal Article] Gelfand EW. Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. (2009)
  • Author(s): Okamoto M, Matsuda H, Lucas JL, Domenico J, Yasutomo K, Takeda K
  • Journal Title: J Immunol Volume: 183 Issue: 5 Pages: 2995-3003
  • DOI: 10.4049/jimmunol.0900692
  • Peer Reviewed
• [Journal Article] Notch activation induces the generation of functional natural killer cells from human cord blood CD34-positive cells devoid of interleukin-15. (2009)
  • Author(s): Haraguchi K, Suzuki T, Koyama N, Kumano K, Nakahara F, Matsumoto A, Yokoyama Y, Sakata-Yanagimoto M, Masuda S, Takahashi T, Kamijo A, Takahashi K, Takanashi M, Okuyama Y, Yasutomo K, Sakano S, Yagita H, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: J Immunol Volume: 182 Issue: 10 Pages: 6168-6178
  • DOI: 10.4049/jimmunol.0803036
  • Peer Reviewed
• [Journal Article] Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells. (2009)
  • Author(s): Kijima M, Iwata A, Maekawa Y, Uehara H, Izumi K, Kitamura A, Yagita H, Chiba S, Shiota H, Yasutomo K
  • Journal Title: J Immunol Volume: 182 Issue: 6 Pages: 3566-3572
  • DOI: 10.4049/jimmunol.0803765
  • Peer Reviewed
• [Journal Article] Notch activation induces the generation of functional natural killer cells from human cord blood CD34-positive cells devoid of interleukin-15. (2009)
  • Author(s): Kyoko Haraguchi
  • Journal Title: The Journal of Immunology 182 Pages: 6168-6178
  • Peer Reviewed
• [Journal Article] Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. (2009)
  • Author(s): Masakazu Okamoto
  • Journal Title: The Journal of Immunology 183 Pages: 2995-3003
  • Peer Reviewed
• [Journal Article] Protein tyrosine phosphatase-kappa regulates CD4+ T cell development through ERK1/2-mediated signaling. (2009)
  • Author(s): Namjil Erdenebayar
  • Journal Title: Biochem Biophys Res Commun 390 Pages: 489-493
  • Peer Reviewed
• [Journal Article] Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells (2009)
  • Author(s): Mika Kijima
  • Journal Title: The Journal of Immunology 182 Pages: 3566-3572
  • Peer Reviewed
• [Journal Article] Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity (2008)
  • Author(s): Yoichi Maekawa
  • Journal Title: Nature Immunology 9 Pages: 1140-1147
  • Peer Reviewed
• [Journal Article] Essential role of Notch signaling in effector memory CD8+T cell-mediated airway hyperresponsiveness and inflammation. (2008)
  • Author(s): Masakazu Okamoto
  • Journal Title: The Journal of Experimental Medicine 12 Pages: 1087-1097
  • Peer Reviewed
• [Journal Article] Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. (2008)
  • Author(s): Mamiko Sakata-Yanagimoto
  • Journal Title: Proc Nat1 Acad Sci USA 105 Pages: 7839-7844
  • Peer Reviewed
• [Journal Article] Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. (2005)
  • Author(s): Maekawa Y, Minato Y, Ishifune C, Kurihara T, Kitamura A, Kojima H, Yagita H, Sakata-Yanagimoto M, Saito T, Taniuchi I, Chiba S, Sone S, Yasutomo K
  • Journal Title: Nature Immunology Volume: 9 Issue: 10 Pages: 1140-1147
  • DOI: 10.1038/ni.1649
  • Peer Reviewed
• [Presentation] 免疫プロテアソーム機能異常による炎症応答の分子基盤 (2012)
  • Author(s): 安友康二
  • Organizer: 日本生化学学会シンポジウム
  • Place of Presentation: 福岡県
  • Year and Date: 2012-12-14
• [Presentation] Notch provides metabolic signals in memory CD4+ T cells (2012)
  • Author(s): Koji Yasutomo
  • Organizer: 日本免疫学会シンポジウム
  • Place of Presentation: 神戸国際会議場、兵庫県
  • Year and Date: 2012-12-02
• [Presentation] Notchシグナルによるリンパ球機能制御 (2010)
  • Author(s): 安友康二
  • Organizer: 宮崎サイエンスキャンプ
  • Place of Presentation: シェラトン・グランデ・オーシャンリゾート(宮崎)
  • Year and Date: 2010-02-28
• [Presentation] Notch signaling controls T cell cytotoxicity (2009)
  • Author(s): 安友康二
  • Organizer: 日本免疫学会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2009-12-03
• [Presentation] Notch controls T cell effector functions (2008)
  • Author(s): 前川洋一
  • Organizer: 日本免疫学会 シンポジウム
  • Place of Presentation: 京都国際会館
  • Year and Date: 2008-12-01
• [Presentation] Notchシグナルによる免疫制御 (2008)
  • Author(s): 安友康二
  • Organizer: 自己免疫疾患研究会
  • Place of Presentation: 東京、霞ヶ関ビル内「東海大学学友会館」
  • Year and Date: 2008-07-12
• [Remarks]
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