神経ペプチドPACAPによる中枢神経系と免疫系間のクロストーク

• Project/Area Number: 26870587
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine; Neurology
• Research Institution: Keio University (2015); Showa University (2014)
• Principal Investigator: 徐 枝芳 慶應義塾大学, 医学部, 研究員 (60646298)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: PACAP / PAC1R / 骨髄造血幹前駆細胞 / 交感神経系

Outline of Annual Research Achievements

2015.4-2015.12まで申請者はPACAPとその受容体が造血組織、特に骨髄における場の全容を明らかにし、PACAPの骨髄における造血幹前駆細胞の作用様式をを明らかにするため、次の三つの基礎研究を行った。1.骨髄におけるPACAP受容体の解剖学的全容（場）の解明：1．骨髄におけるPACAP特異的レセプター(PAC1R)の遺伝子発現が骨髄に認められることを見出した。マウスの凍結切片を用いた免疫染色及びフローサイトメトリーでによりPAC1Rが骨髄造血細胞に認められ、未熟な骨髄細胞や成熟した細胞では極めて低いことからPACAP- PAC1Rシグナルは造血過程に関与する可能性を見出した。PAC1R陽性細胞はCD34、CD117、Sca-1の陽性細胞をセールソータで分離し、PAC1の遺伝子発現が造血幹前駆細胞マーカーと共存することを見出した。2．PACAPによる造血能の作用様式の解明：マウスの骨髄造血幹前駆細胞の比率をフローサイトメトリーで解析した。その結果、野生型マウスに比べて、PACAP　KOマウスでは骨髄造血幹前駆細胞の割合が低かった。これらの結果より、PACAPは交感神経系から骨髄に放出され、造血機構の制御に関与していると示唆される。3．マウスの骨髄造血幹前駆細胞（CD34+及びCD34+/Sca-1+）をセルソーターにより分離、造血幹前駆細胞の増殖及び分化に対するPACAPの役割をフローサイトメトリー及びCFU-assayにより調べた。さらに、PAC1Rのアゴニスト、アンタゴニストを用いて、造血幹前駆細胞に与える影響を確認した。これらの結果より、交感神経系からPACAPが放出され、レセプターPAC1Rを介して、骨髄における造血幹前駆細胞の増殖を制御していると示唆される。

Research Products

• [Journal Article] Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP). (2015)
  • Author(s): Tsumuraya T, Ohtaki H, Song D, Sato A, Watanabe J, Hiraizumi Y, Nakamachi T, Xu Z, Dohi K, Hashimoto H, Atsumi T, Shioda S.
  • Journal Title: J Neuroinflammation. Volume: 12(1) Issue: 1 Pages: 35-35
  • DOI: 10.1186/s12974-015-0252-5
  • Peer Reviewed / Open Access
• [Journal Article] Panax notoginseng saponins alleviate the cerebral edema of rats with intracerebral hemorrhage via coagulation cascade pathway. (2014)
  • Author(s): Xuesong Zhao, Zhigang Chen, Fang Gao, Zhifang Xu.
  • Journal Title: Chinese Journal of Information on Traditional Chinese Medicine Volume: 21 Pages: 46-48
  • Peer Reviewed
• [Journal Article] PACAP38 suppresses cortical damage in mice with traumatic brain injury by enhancing antioxidant activity. (2014)
  • Author(s): Miyamoto K, Tsumuraya T, Ohtaki H, Dohi K, Satoh K, Xu Z, Tanaka S, Murai N, Watanabe J, Sugiyama K, Aruga T, Shioda S.
  • Journal Title: J Mol Neurosci. Volume: 54(3) Issue: 3 Pages: 370-379
  • DOI: 10.1007/s12031-014-0309-4
  • Peer Reviewed
• [Presentation] PACAP/PAC1 pathway contributes to the proliferation of hematopoietic stem/progenitor cells in murine bone marrow with special reference to sympathetic innervation. (2015)
  • Author(s): XU Zhifang, Jinushi Masahisa, Kawakami Yutaka.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] PACAP contributes to proliferation of hematopoietic stem/progenitor cells in murine bone marrow. (2015)
  • Author(s): Zhifang Xu, Hirokazu Ohtaki, Jun Watanabe, Yutaka Hiraizumi, Hitoshi Hashimoto, Satoshi Numazawa, Seiji Shioda.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: Kapadokya 、Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] The role of neuropeptide PACAP in the proliferation of hematopoietic stem/progenitor cells in murine bone marrow. (2015)
  • Author(s): Zhifang Xu, Hirokazu Ohtaki, Jun Watanabe, Yutaka Hiraizumi, Satoshi Numazawa, Seiji Shioda.
  • Organizer: 第36回日本炎症∙再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-07-21
• [Presentation] PACAP contributes to the proliferation of hematopoietic stem/progenitor cells in murine bone marrow via its specific receptor PAC1. (2015)
  • Author(s): Zhifang Xu, Hirokazu Ohtaki, Jun Watanabe, Tomoya Nakamachi, Satoshi Numazawa, Seiji Shioda.
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 日本科学未来館 未来館ホール(東京都江東区）
  • Year and Date: 2015-05-15
• [Presentation] Effect of human mesenchymal stem cells (hMSCs) administrated into pancreases on diabetic mice. (2015)
  • Author(s): Murai N, Ohtaki H, Watanabe J, Xu Z, Sasaki S, Matsumoto M, Izumizaki M, Shioda S
  • Organizer: 第120回 日本解剖学会総会･全国学術集会・第92回 日本生理学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Role of neuropeptide PACAP in hematopoiesis via its specific receptor PAC1R (2015)
  • Author(s): Xu Z, Ohtaki H, Watanabe J, Hiraizumi Y, Numazawa S, Shioda S
  • Organizer: 第120回 日本解剖学会総会･全国学術集会・第92回 日本生理学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] The distribution of PACAP receptor on the sweat glands (2015)
  • Author(s): Sasaki S, Ohtaki H, Watanabe J, Xu Z, Murai N, Matsumoto M, Shioda S
  • Organizer: 第120回 日本解剖学会総会･全国学術集会・第92回 日本生理学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] 糖尿病モデルマウスに対するヒト骨髄由来間葉系幹細胞(hMSCs)の膵臓内投与による有用性の検討. (2014)
  • Author(s): 村井謙允, 大滝博和, 渡邊潤, 徐枝芳, 佐々木駿, 松本皆子, 泉崎雅彦, 塩田清二.
  • Organizer: 日本解剖学会関東支部 第102回学術集会
  • Place of Presentation: 東京医科大学病院
  • Year and Date: 2014-11-22
• [Presentation] PACAP receptor expression of hematopoietic stem/progenitor cells in mouse bone marrow with special reference to sympathetic innervation (2014)
  • Author(s): Z XU, S TANAKA, H OHTAKI, J WATANABE, Y HIRAIZUMI, S NUMAZAWA, S SHIODA.
  • Organizer: Neuroscience 2014
  • Place of Presentation: Convention Center, Washington D.C.
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] PACAP induces differentiation of neural progenitor cells into glial lineage in cerebral cortex development (2014)
  • Author(s): J WATANABE, H OHTAKI, T NAKAMACHI, Z XU, K SUGIYAMA, S SASAKI, S ARATA, S SHIODA
  • Organizer: Neuroscience 2014
  • Place of Presentation: Convention Center, Washington D.C.
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Implantation of human mesenchymal stem/progenitor cells (hMSCs) from bone marrow suppresses spinal cord injury mediated by pituitary adenylate cyclase activating polypeptide (PACAP) (2014)
  • Author(s): H OHTAKI, T TSUMURAYA, A SATO, Z XU, J WATANABE, M MATSUMOTO, N MURAI, H HASHIMOTO, Y HIRAIZUMI, T NAKAMACHI, S SHIODA
  • Organizer: Neuroscience 2014
  • Place of Presentation: Convention Center, Washington D.C.
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Suppression of spinal cord injury on human mesenchymal stem/progenitor cells (MSCs) mediated by pituitary adenylate cyclase activating polypeptide (PACAP). (2014)
  • Author(s): Ohtaki H, Tsumuraya T, Sato A, Xu Z, Miyamoto K, Watanabe J, Nakamachi T, Hashimoto H, Shioda S.
  • Organizer: 12th International Congress of Neuroimmunology
  • Place of Presentation: Mainz, Germany
  • Year and Date: 2014-11-09 – 2014-11-13
• [Presentation] The role of neuropeptide PACAP in the crosstalk between central nervous system and hematopoiesis (2014)
  • Author(s): Zhifang Xu, Hirokazu Ohtaki, Jun Watanabe, Tomoya Nakamachi, Kenji Dohi, Seiji Shioda
  • Organizer: The 11th China-Japan Joint Seminar Histochemistry and Cytochemistry
  • Place of Presentation: 松本中央公民館
  • Year and Date: 2014-09-27 – 2014-09-29
  • Invited
• [Presentation] PACAP type 1 receptor expression in hematopoietic stem/progenitor cells of mouse bone marrow with special reference to sympathetic innervation (2014)
  • Author(s): Zhifang Xu, Hirokazu Ohtaki, Jun Watanabe, Yutaka Hiraizumi, Satoshi Numazawa, Seiji Shioda
  • Organizer: 20th International Symposium on Regulatory Peptides
  • Place of Presentation: Kyoto Garden Palace
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] Human mesenchymal stem/progenitor cells (hMSCs) suppress neural cell damage mediated by tuning of microglia/macrophage activation. (2014)
  • Author(s): Ohtaki H, Tsumuraya T, Sato A, Watanabe J, Xu Z, Hiraizumi Y, Shioda S.
  • Organizer: Cold Spring Harbor Symposium (CSHS), Glia in Health & Disease
  • Place of Presentation: Cold Spring Harbor Institute, Cold Spring Harbor, NY
  • Year and Date: 2014-07-17 – 2014-07-21
• [Presentation] Expression and localization of PACAP specific receptor (PAC1R) in bone marrow of mice (2014)
  • Author(s): 徐 枝芳、大滝 博和、渡邊 潤、宮本 和幸、村井謙允、中町 智哉、平泉 裕、沼澤 聡、塩田 清二
  • Organizer: 第35回日本炎症再生医学会
  • Place of Presentation: 沖縄万国津梁館
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] Expression and localization of PACAP specific receptor PAC1R in mouse bone marrow. (2014)
  • Author(s): 徐 枝芳、大滝 博和、渡邊 潤、宮本 和幸、村井謙允、中町 智哉、平泉 裕、沼澤 聡、塩田 清二
  • Organizer: 第11回GPCR研究会
  • Place of Presentation: 東京日本科学未来館
  • Year and Date: 2014-05-09 – 2014-05-10
• [Book] "Handbook of Hormones, 1st Edition Comparative Endocrinology for Basic and Clinical Research ". Eds: Yoshio Takei, Hironori Ando, Kazuyoshi Tsutsu. (2015)
  • Author(s): Zhifang Xu
  • Total Pages: 674
  • Publisher: Academic Press