Molecular basis of the CD47-SIRP alpha signaling system in the regulation of physiological function

• Project/Area Number: 26291022
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kobe University
• Principal Investigator: Matozaki Takashi 神戸大学, 医学(系)研究科(研究院), 教授 (80252782)
• Co-Investigator(Renkei-kenkyūsha): OHNISHI Hiroshi 群馬大学, 大学院保健学研究科, 教授 (70334125) ; MURATA Yoji 神戸大学, 大学院医学研究科, 准教授 (60400735) ; SAITO Yasuyuki 神戸大学, 大学院医学研究科, 講師 (40508842) ; KOTANI Takenori 神戸大学, 大学院医学研究科, 助教 (40455960)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: シグナル伝達 / 生体分子 / 脳・神経 / 免疫学 / 癌

Outline of Final Research Achievements

We have here investigated the molecular basis of the CD47-SIRPα signaling system in the regulation of physiological function in the central nervous system (CNS) as well as in the immune system. In the CNS, we have shown that the protein tyrosine phosphatase Shp-2, which is a downstream molecule of SIRPα, regulates synaptic functions and thereby modulates learning and locomotor activity. In the immune system, we have shown that SIRPα is essential for the maintenance of dendritic cell homeostasis in the secondary lymphoid organs and skin. Furthermore, we have found that anti-SIRPα antibodies appear to be a potential new tool for cancer immunotherapy.

Research Products

• [Journal Article] Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. (2017)
  • Author(s): Yanagita T, Murata Y, Tanaka D, Motegi S, Arai E, Daniwijaya EW, Hazama D, Washio K, Saito Y, Kotani T, Ohnishi H, Oldenborg PA, Verjan Garcia N, Miyasaka M, Ishikawa O, Kanai Y, Komori T, Matozaki T.
  • Journal Title: JCI Insight Volume: 2 Issue: 1
  • DOI: 10.1172/jci.insight.89140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Src family kinases in regulation of intestinal epithelial homeostasis. (2016)
  • Author(s): Imada S, Murata Y, Kotani T, Hatano M, Sun C, Konno T, Park JH, Kitamura Y, Saito Y, Ohdan H, Matozaki T.
  • Journal Title: Mol Cell Biol Volume: 36 Issue: 22 Pages: 2811-2823
  • DOI: 10.1128/mcb.00311-16
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lack of SIRPα phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation. (2016)
  • Author(s): Holm CK, Engman S, Sulniute R, Matozaki T, Oldenborg PA, Lundberg P.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 1 Pages: 268-273
  • DOI: 10.1016/j.bbrc.2016.07.048
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium (2015)
  • Author(s): Y Murata, T Kotani, Y Supriatna, Y Kitamura, S Imada, K Kawahara, M Nishio, EW Daniwijaya, H Sadakata, S Kusakari, M Mori, Y Kanazawa, Y Saito, K Okawa, M Takeda-Morishita, H Okazawa, H Ohnishi, T Azuma, A Suzuki, T Matozaki
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 31
  • DOI: 10.1073/pnas.1510167112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen. (2015)
  • Author(s): Kolan SS, Lejon K, Koskinen Holm C, Sulniute R, Lundberg P, Matozaki T, Oldenborg PA.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0134113-e0134113
  • DOI: 10.1371/journal.pone.0134113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of Phagocyte Migration by Signal Regulatory Protein-Alpha Signaling. (2015)
  • Author(s): Alvarez-Zarate J, Matlung HL, Matozaki T, Kuijpers TW, Maridonneau-Parini I, van den Berg TK.
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0127178-e0127178
  • DOI: 10.1371/journal.pone.0127178
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs (2015)
  • Author(s): Washio K, Kotani T, Saito Y, Respatika D, Murata Y, Kaneko Y, Okazawa H, Ohnishi H, Fukunaga A, Nishigori C, Matozaki T.
  • Journal Title: Genes Cells Volume: - Issue: 6 Pages: 00-00
  • DOI: 10.1111/gtc.12238
  • Peer Reviewed / Open Access
• [Journal Article] Regulation by gut commensal bacteria of carcinoembryonic antigen-related cell adhesion molecule expression in the intestinal epithelium (2015)
  • Author(s): Kitamura Y, Murata Y, Park JH, Kotani T, Imada S, Saito Y, Okazawa H, Azuma T, Matozaki T.
  • Journal Title: Genes Cells. Volume: - Issue: 7 Pages: 578-589
  • DOI: 10.1111/gtc.12247
  • Peer Reviewed / Open Access
• [Journal Article] Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst (2015)
  • Author(s): Li XJ, Goodwin CB, Nabinger SC, Richine BM, Yang Z, Hanenberg H, Ohnishi H, Matozaki T, Feng GS, Chan RJ.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 7 Pages: 3894-3909
  • DOI: 10.1074/jbc.m114.614057
  • Peer Reviewed
• [Journal Article] Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice (2015)
  • Author(s): Kusakari S, Saitow F, Ago Y, Shibasaki K, Sato-Hashimoto, M., Matsuzaki, Y., Kotani T, Murata Y, Hirai H, Matsuda T, Suzuki H, Matozaki T, Ohnishi H
  • Journal Title: Mol. Cell. Biol. Volume: 35 Issue: 9 Pages: 1557-1572
  • DOI: 10.1128/mcb.01339-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells (2015)
  • Author(s): Kolan SS, Boman A, Matozaki T, Lejon K, Oldenborg PA.
  • Journal Title: Biochem Biophys Res Commun. Volume: 460 Issue: 3 Pages: 645-650
  • DOI: 10.1016/j.bbrc.2015.03.084
  • Peer Reviewed
• [Journal Article] Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor (2014)
  • Author(s): Yoshino S, Satoh T, Yamada M, Hashimoto K, Tomaru T, Katano-Toki A, Kakizaki S, Okada S, Shimizu H, Ozawa A, Tuchiya T, Ikota H, Nakazato Y, Mori M, Matozaki T, Sasaki T, Kitamura T, Mori M.
  • Journal Title: Endocrinology. Volume: 155 Issue: 9 Pages: 3459-3472
  • DOI: 10.1210/en.2013-2160
  • Peer Reviewed
• [Presentation] Role of SIRPα on dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
• [Presentation] Human hemato-lymphoid system development in human cytokine knock-in mice engrafted with adult donor-derived CD34+ cells (2016)
  • Author(s): Yasuyuki Saito, Takashi Matozaki, Richard A. Flavell, Markus G. Manz
  • Organizer: 第12回プロテインホスファターゼ国際カンファレンス ＆ 革新がんゲノム国際シンポジウム
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Therapeutic application of anti-SIRPαantibody in cancer treatment (2016)
  • Author(s): Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Yasuyuki Saito, Takenori Kotani, Takahide Komori, Takashi Matozaki
  • Organizer: 第12回プロテインホスファターゼ国際カンファレンス ＆ 革新がんゲノム国際シンポジウム
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Role of SIRPαin the homeostasis of fibroblastic reticular cells by dendritic cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第12回プロテインホスファターゼ国際カンファレンス ＆ 革新がんゲノム国際シンポジウム
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Development of novel cancer immunotherapy targeting tumor microenvironment/がん微小環境を利用した新しいがん免疫療法の開発 (2016)
  • Author(s): 的崎 尚
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] The anti-SIRPα antibody prevents tumor formation: a novel strategy for cancer therapy /抗SIRPα抗体を用いた新たながん治療法 (2016)
  • Author(s): 栁田 匡彦、村田 陽二、田中 大介、齊藤 泰之、小谷 武徳、古森 孝英、的崎 尚
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] 細胞間シグナルCD47-SIRPα系の生理機能とその臨床応用/Role of the CD47-SIRPalpha system and its therapeutic application (2016)
  • Author(s): 的崎 尚、村田 陽二、齊藤 泰之、小谷 武徳、栁田 匡彦、田中 大介、大西 浩史
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-26
• [Presentation] 白質におけるミクログリア恒常性制御 (2016)
  • Author(s): 野津 智美、橋本 美穂、Ruwaida Elhanbaly、石川 達也、齊藤 泰之、小谷 武徳、村田 陽二、深澤 有吾、的崎 尚、大西 浩史
  • Organizer: 第38回日本生物学的精神医学会、第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-09-08
• [Presentation] SIRPα欠損マウスはLPS投与によって誘導される低体温症が重症化する (2016)
  • Author(s): 橋本 美穂、野津 智美、浦野 江里子、齊藤 泰之、小谷 武徳、村田 陽二、的崎 尚、大西 浩史
  • Organizer: 第38回日本生物学的精神医学会、第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-09-08
• [Presentation] Role of SIRPαon dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第15回生体機能研究会
  • Place of Presentation: 淡路夢舞台国際会議場
  • Year and Date: 2016-07-01
• [Presentation] Essential Role of SIRPα on Dendritic Cells in Homeostatic Regulation of Spleen Stromal Cells (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第7回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 基礎生物学研究所（愛知県・岡崎市）
  • Year and Date: 2016-01-29
• [Presentation] 細胞間シグナルCD47-SIRPα系の生理機能と臨床応用 (2016)
  • Author(s): 的崎 尚
  • Organizer: 第1回徳島大学・神戸大学連携シンポジウム
  • Place of Presentation: 神戸大学神緑会館
• [Presentation] Essential role of SIRPα on dendritic cells in Homeostatic regulation of the secondary lymphoid organ (2015)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Atsushi Fukunaga, Chikako Nishigori, and Takashi Matozaki
  • Organizer: 2015University of Washington and Kobe University joint symposium 2015神戸大学・ワシントン大学国際合同シンポジウム
  • Place of Presentation: University of Washington, Seattle （USA）
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] Regulation of dendritic cell and stromal-cell homeostasis by dendritic cell-SIRPα in the spleen (2015)
  • Author(s): Yasuyuki Saito
  • Organizer: 2015University of Washington and Kobe University joint symposium 2015神戸大学・ワシントン大学国際合同シンポジウム
  • Place of Presentation: University of Washington, Seattle （USA）
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] SAP-1 and CEACAM20 protect against colitis in the intestinal epithelium (2015)
  • Author(s): Yoji Murata, Takenori Kotani, Yana Supriatna, Yasuaki Kitamura, Shinya Imada, Yasuyuki Saito, Hideki Okazawa, Hiroshi Ohnishi, Takashi Matozaki
  • Organizer: FASEB
  • Place of Presentation: The Steamboat Grand, SteamboatSprings （USA）
  • Year and Date: 2015-08-02
  • Int'l Joint Research
• [Presentation] Role of C-terminal Src kinase(Csk) and Src family kinases in homeostasis of the intestinal epithelium (2015)
  • Author(s): Shinya Imada, Yoji Murata, Yasuaki Kitamura, Jung-ha Park, Masaki Hatano, Takenori Kotani, Yasuyuki Saito, Hideki Ohdan, Takashi Matozaki
  • Organizer: FASEB
  • Place of Presentation: The Steamboat Grand, SteamboatSprings （USA）
  • Year and Date: 2015-08-02
  • Int'l Joint Research
• [Presentation] Behavioral analysis of forebrain neuron-specific Shp2 conditional knockout mice/前脳神経細胞特異的Shp2コンディショナルKOﾏｳｽの行動解析 (2015)
  • Author(s): Hiroshi Ohnishi, Shinya Kusakari, Miho Sato-Hashimoto, Shuya Ishikawa, Eriko Urano, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: Neuroscience 2015 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場/神戸国際展示場（兵庫県・神戸市）
  • Year and Date: 2015-07-28
• [Presentation] Analysis of cell-cell interaction signal that regulates microglial homeostasis/ミクログリア恒常性を制御する細胞間相互作用シグナルの解析 (2015)
  • Author(s): Miho Sato-Hashimoto, Tomomi Nozu, Eriko Urano, Takenori Kotani, Yoji Murata, Takashi Matozaki, Hiroshi Ohnishi
  • Organizer: Neuroscience 2015 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場/神戸国際展示場（兵庫県・神戸市）
  • Year and Date: 2015-07-28
• [Presentation] 異種間移植におけるCD47-SIRPα系の役割とその応用 (2015)
  • Author(s): 齊藤 泰之、的崎 尚
  • Organizer: 第14回生体機能研究会
  • Place of Presentation: ザ・プリンス箱根（神奈川県・箱根町）
  • Year and Date: 2015-07-25
• [Presentation] 細胞間シグナル伝達システムCD47-SIRPα系のがん治療への応用 (2015)
  • Author(s): 栁田 匡彦、村田 陽二、田中 大介、小谷 武徳、齊藤 泰之、古森 孝英、的崎 尚
  • Organizer: 第14回生体機能研究会
  • Place of Presentation: ザ・プリンス箱根（神奈川県・箱根町）
  • Year and Date: 2015-07-25
• [Presentation] Essential role of SIRPα on dendritic ｃells in organization and homeostasis of the spleen (2014)
  • Author(s): Ken Washio, Takenori Kotani, Datu Respatika, Yoji Murata, Yasuyuki Saito, Hideki Okazawa, Hiroshi Ohnishi, Atsushi Fukunaga, Chikako Nishigori, Takashi Matozaki
  • Organizer: 第43回日本免疫学会 学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Immunological analysis of autoimmune nephritis observed in DC-specific Shp1 conditional knockout mice (2014)
  • Author(s): Mitsuharu Watanabe, Yoriaki Kaneko, Keiju Hiromura, Yuko Ohishi, Masato Kinoshita, Ohnishi Hiroshi, Takashi Matozaki, Yoshihisa Nojima
  • Organizer: 第43回日本免疫学会 学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 細胞間コミュニケーションシステムCD47-SIRPα系による血液・免疫系の制御 / Regulation by CD47-SIRPα signaling of hematopoietic and immune systems (2014)
  • Author(s): 小谷武徳、鷲尾健、ダトゥレスパティカ、村田陽二、齊藤泰之、的崎尚
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Functinal analysis of protein tyrosine phosphatase Shp2 in post-mitotic neurons (2014)
  • Author(s): Shinya Kusakari, Fumihito Saitow, Miho Hashimoato, Yasunori Matsuzaki , Takenori Kotani, Yoji Murata, Hirokazu Hirai, Hidenori Suzuki, Takashi Matozaki, Hiroshi Ohnishi
  • Organizer: 第11回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 東北大学医学部 艮陵会館（宮城県・仙台市）
  • Year and Date: 2014-11-12 – 2014-11-14
• [Presentation] Roles of protein tｙrosine phosphatases in homeostasis of intestinal epithelium (2014)
  • Author(s): Takashi Matozaki, Yoji Murata, Takenori Kotani, Yasuyuki Saito
  • Organizer: 第11回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 東北大学医学部 艮陵会館（宮城県・仙台市）
  • Year and Date: 2014-11-12 – 2014-11-14
• [Presentation] Functional Analysis of protein tyrosine phosphatase Shp2 in the adult forebrain neurons (2014)
  • Author(s): Hiroshi Ohnishi, Shinya Kusakari, Fumihito Saitow, Miho Hashimoto, Yasunori Matsuzaki, Takenori Kotani, Yoji Murata, Hirokazu Hirai, Hidenori Suzuki, Takashi Matozaki
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Regulation of microglial homeostasis through cell-cell interaction signal (2014)
  • Author(s): Miho Sato-Hashimoto, Yuriko Hayashi, Shinya Kusakari, Takenori Kotani, Yoji Murata, Takashi Matozaki, Hiroshi Ohnishi
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 樹状細胞及び二次リンパ組織の恒常維持におけるSIRPαの役割 (2014)
  • Author(s): 鷲尾健、小谷武徳、レスパティカ ダトゥ、村田陽二、齊藤泰之、金子和光、岡澤秀樹、大西浩史、福永淳、錦織千佳子、的崎尚
  • Organizer: 第13回生体機能研究会
  • Place of Presentation: ホテルパーク /岐阜長良川温泉（岐阜県・岐阜市）
  • Year and Date: 2014-07-18 – 2014-07-19
• [Remarks] 神戸大学大学院医学研究科 生化学・分子生物学講座 シグナル統合学分野
  • URL: http://www.med.kobe-u.ac.jp/tougou/signal/Home.html
• [Patent(Industrial Property Rights)] 抗腫瘍剤 (2016)
  • Inventor(s): 的崎 尚、村田陽二
  • Industrial Property Rights Holder: 的崎 尚、村田陽二
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-133638
  • Filing Date: 2016-07-05