iPS細胞とヒト疾患モデルマウスを用いたSTAT1シグナル異常症の病態解析

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26670501
• Research Institution: Hiroshima University
• Principal Investigator: 小林 正夫 広島大学, 医歯薬保健学研究院(医), 教授 (00162016)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: STAT1 / iPS細胞 / 単球機能 / 破骨細胞

Outline of Annual Research Achievements

転写因子STAT1異常症はSTAT1遺伝子の機能喪失型変異と機能獲得型変異があり，それぞれ異なった表現型を示すことが知られている。それぞれの患者から疾患特異的iPS細胞を樹立し，iPS細胞を造血系から骨髄系細胞への分化を行い，最終的には単球系への分化を試みた。機能喪失型変異は主として単球系細胞の機能異常が認められるので，iPS細胞からの分化した単球を用いた機能解析を行った。単球でのIFNγ刺激に対するSTAT1分子のリン酸化異常をiPS細胞で確認出来たが，転写活性の低下まで確認することは現段階では確立されていない。患者細胞とiPS細胞での分化した細胞で十分に病態を反映できているか，今後の検討が必要である。また，患者骨髄細胞からの破骨細胞への分化を行い，機能喪失型では正常コントロールと比較してより活性の高い破骨細胞が多く誘導されることを確認した。現在iPS細胞からの破骨細胞への分化を試みている。また機能獲得型変異から樹立したiPS細胞を用いた，単球分化でのSTAT1分子のリン酸化の亢進について検討を継続している。それぞれの異常からの樹立したiPS細胞を用いて，単球系細胞でのSTAT1分子のリン酸化の低下と亢進を確認することで，病態の一部を反映することが可能となるであろう。

Research Products

• [Journal Article] Impairment of IL-17A/F immunity to Candida and IFN-γ immunity to Mycobacterium in humans with inherited RORγT deficiency. (2015)
  • Author(s): Okada S, Markle JG, Deenick EK, Federico Mele F, Averbuch D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL
  • Journal Title: Science Volume: 349 Pages: 606-613
  • DOI: 10.1126/science.aaa4282.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. (2015)
  • Author(s): Hirata O, Okada S, Tsumura M, Ohtsubo M, Karakawa S, Matsumura I, Kimura Y, Maihara T, Yasunaga S, Takihara Y, Ohara O, Kobayashi M:
  • Journal Title: Journal of Clinical Immunology Volume: 35 Pages: 512-516
  • DOI: 10.1007/s10875-015-0165-1.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia. (2015)
  • Author(s): Narita A, Muramatsu H, Sekiya Y, Okuno Y, Sakaguchi H, Nishio N, Yoshida N, Wang X, Xu Y, Kawashima N, Doisaki S, Hama A, Takahashi Y, Kudo K, Moritake H, Kobayashi M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S.
  • Journal Title: Haematologica Volume: 100 Pages: 1546-1552
  • DOI: 10.3324/haematol.2015.132530.
  • Peer Reviewed / Open Access
• [Journal Article] STAT3 is a critical cell intrinsic regulator of human unconventional T cell numbers and function. (2015)
  • Author(s): Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Holland SM, Casanova JL, Uzel G, Ma CS, Tangye SG, Deenick EK
  • Journal Title: Journal of Experimental Medicine Volume: 212 Pages: 855-864
  • DOI: 10.1084/jem.20141992.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies. (2015)
  • Author(s): Ma, CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, Bustamate J, Okada S, Stoddard JL, Deenick EK, Pelham SJ, Payne K, Boisson-Dupuis S, Puel A, Kobayashi M, Arkwright PD, Kilic SS, Baghdadi JE, Nonoyama S, Minegishi Y, Holland SM, Casanova JL, Uzel G, Tangye S
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 136 Pages: 993-1006
  • DOI: 10.1016/j.jaci.2015.05.036.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Impairment of IL-17 immunity to Candida and IFNγ immunity to Mycobacterium in humans with bi-allelic Rorc mutations. (2015)
  • Author(s): Okada S, Markle J, Kobayashi M, Bustamante J, Casanova JL
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05 – 2015-12-08
  • Int'l Joint Research
• [Presentation] MSMD Patients with IFN-γ-STAT1 Signaling Defect Present Enhanced Osteoclastogenesis and Bone Resorption. (2015)
  • Author(s): Nishimura S, Tsumura M, Hirata O, Reiko Kagawa, Mizoguchi Y, Okada S, Kobayashi M
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05 – 2015-12-08
  • Int'l Joint Research
• [Presentation] A comparison of myelopoiesis from induced pluripotent stem cells with a mutation in ELANE between cyclic neutropenia and sever congenital neutropenia. (2015)
  • Author(s): Saito S, Nishimura S, Tsumra M, Mizoguchi Y, Sakata S, Furue A, Kobayashi M
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05 – 2015-12-08
  • Int'l Joint Research
• [Presentation] 好中球異常症：診断と造血幹細胞移植 (2015)
  • Author(s): 小林正夫
  • Organizer: 第77回日本血液学会教育講演
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16 – 2015-10-18
  • Invited