Exploring pathophysiology of sepsis based on the mechanism of granulopoiesis regulated by the C/EBPbeta transcription factor

• Project/Area Number: 23592678
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SHIME NOBUAKI 京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (00260795)
• Co-Investigator(Kenkyū-buntansha): HIRAI Hideyo 京都大学, 医学研究科, 講師 (50315933)
• Research Collaborator: SATAKE Sakiko 京都大学
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 好中球 / 分化/増殖 / C/EBPβ / 造血幹細胞 / 敗血症 / カンジダ / cEBP/β / 感染 / 炎症 / 機能制御 / 文化/増殖 / Ｃ/ＦＢＰ β

Outline of Final Research Achievements

CCAAT/enhancer-binding protein β(C/EBPβ) could play crucial roles on cellular differentiation and functional maintenance in various types of somatic cells. Granulocyte production increases in response to increased neutrophil demand following infectious stress. In this study, we investigated the role of C/EBPβ at hematopoietic stem cell levels in stress-induced granulopoiesis. C/EBPβ was upregulated at the protein level in all the five distinct subpopulations of granulopoiesis in a mouse candidemia model. Using a C/EBPβ knockout mouse model, the role of C/EBPβ in cell cycle acceleration and proliferation of hematopoietic stem/progenitors was also confirmed. These data suggest that C/EBPβ is a significant controlling factor involved in the efficient amplification of early granulocyte precursors during emergency granulopoiesis.

Research Products

• [Journal Article] Non-steady-state hematopoiesis regulated by the C/EBPbeta transcription factor. (2015)
  • Author(s): Hirai H, et al.
  • Journal Title: Cancer Science Volume: *
  • Peer Reviewed
• [Journal Article] CCR1-mediated Accumulation of Myeloid Cells in the Liver Microenvironment Promoting Mouse Colon Cancer Metastasis (2014)
  • Author(s): Hirai H, et al
  • Journal Title: Clinical and Experimental Metastasis Volume: 32 Issue: 8 Pages: 2245-55
  • DOI: 10.1002/stem.1701
  • Peer Reviewed / Open Access
• [Journal Article] 敗血症性ショックにおける感染症診断と抗菌治療 (2014)
  • Author(s): 志馬伸朗
  • Journal Title: 化学療法の領域 Volume: 30 Pages: 631-640
• [Journal Article] Invasive pulmonary aspergillosis in a patient presenting with idiopathic systemic capillary leak syndrome. (2014)
  • Author(s): Hayama M, Shime N, et al
  • Journal Title: BMJ Case Rep Volume: May 23 Pages: bcr2014203764-bcr2014203764
  • DOI: 10.1136/bcr-2014-203764
  • Peer Reviewed
• [Journal Article] A pilot study of Bifidobacterium breve in neonates undergoing surgery for congenital heart disease. (2014)
  • Author(s): Umenai T, Shime N, et al
  • Journal Title: Journal of Intensive Care Volume: 2 Pages: 36-36
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Respiratory rate criteria for pediatric systematic inflammatory response syndrome. (2014)
  • Author(s): Nakagawa S, Shime N
  • Journal Title: Pediatr Crit Care Med Volume: 15 Issue: 2 Pages: 182-182
  • DOI: 10.1097/pcc.0000000000000024
  • Peer Reviewed
• [Journal Article] Evaluation of semi-quantitative scoring of Gram staining or semi-quantitative culture for the diagnosis of ventilator-associated pneumonia: a retrospective comparison with quantitative culture. (2014)
  • Author(s): Hashimoto S, Shime N
  • Journal Title: J Intensive Care Volume: 1 Pages: 2-2
  • Peer Reviewed
• [Journal Article] CCAAT/Enhancer-Binding Protein β Expressed by Bone Marrow Mesenchymal Stromal Cells Regulates Early B-Cell Lymphopoiesis (2014)
  • Author(s): Yoshioka S, Miura Y, Yao H, Satake S, Hayashi Y, Tamura A, Hishita T, Ichinohe T, Hirai H, Takaori-Kondo A, Maekawa T
  • Journal Title: Stem Cells Volume: 32 Issue: 3 Pages: 730-740
  • DOI: 10.1002/stem.1555
  • Peer Reviewed
• [Journal Article] 好中球分化異常と疾患 (2013)
  • Author(s): 平位秀世
  • Journal Title: 臨床血液 Volume: 54 Pages: 27-38
  • NAID: 10031196300
  • Peer Reviewed
• [Journal Article] Cyclic AMP responsive element binding proteins are involved in 'emergency' granulopoiesis through the upregulation of CCAAT/enhancer binding protein β. (2013)
  • Author(s): Hirai H
  • Journal Title: PLoS One Volume: 8 Issue: 1 Pages: e54862-e54862
  • DOI: 10.1371/journal.pone.0054862
  • NAID: 120005242481
  • Peer Reviewed
• [Journal Article] C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion. (2013)
  • Author(s): 5. Hayashi Y, Hirai H, Kamio N, Yao H, Yoshioka S, Miura Y, Ashihara E, Fujiyama Y, Tenen DG, Maekawa T.
  • Journal Title: Leukemia Volume: 27 Issue: 3 Pages: 619-628
  • DOI: 10.1038/leu.2012.258
  • NAID: 120005466670
  • Peer Reviewed
• [Journal Article] Incidence and risk factors for mortality in paediatric severe sepsis: results from the national paediatric intensive care registry in Japan. (2012)
  • Author(s): Shime N, et al
  • Journal Title: Intensive Care Med Volume: 38 Issue: 7 Pages: 1191-7
  • DOI: 10.1007/s00134-012-2550-z
  • Peer Reviewed
• [Journal Article] C/EBP is involved in the amplification of early granulocyte precursors during candidemia-induced ‘emergency’ granulopoiesis. (2012)
  • Author(s): Satake S
  • Journal Title: J Immunol Volume: 198 Issue: 9 Pages: 4546-4555
  • DOI: 10.4049/jimmunol.1103007
  • Peer Reviewed
• [Journal Article] Current practices for ventilator-associated pneumonia prevention in Japan: a survey study (2012)
  • Author(s): Shime N, et al
  • Journal Title: Chest Volume: 141 Pages: 281-3
  • Peer Reviewed
• [Journal Article] Mechanically ventilated children with 2009 pandemic influenza A/H1N1: Results from the national pediatric intensive care registry in Japan (2012)
  • Author(s): Tokuhira N, Shime N, et al
  • Journal Title: Pediatr Crit Care Med Volume: 13
  • Peer Reviewed
• [Journal Article] De-escalation of antimicrobials in the treatment of bacteraemia due to antibiotic-sensitive pathogens in immunocompetent patients. (2011)
  • Author(s): Shime N, Satake S, et al.
  • Journal Title: nfection Volume: 39 Issue: 4 Pages: 319-25
  • DOI: 10.1007/s15010-011-0116-6
  • Peer Reviewed
• [Journal Article] Fast-track postoperative care for neonatal cardiac surgery: a single-institute experience (2011)
  • Author(s): Yamasaki Y, Shime N, et al.
  • Journal Title: J Anesth Volume: 25 Issue: 3 Pages: 321-9
  • DOI: 10.1007/s00540-011-1130-7
  • NAID: 10029022846
  • Peer Reviewed
• [Journal Article] De-escalation strategies could be applied to a wide variety of infectious settings (2011)
  • Author(s): Shime N
  • Journal Title: Infection Volume: 40 Issue: 2 Pages: 229-230
  • DOI: 10.1007/s15010-011-0222-5
  • Peer Reviewed
• [Journal Article] Rapid automated detection of ABL kinase domain mutations in imatinib-resistant patients (2011)
  • Author(s): Tanaka, R., Kimura, S., Ashihara, E., Yoshimura, M., Takahashi, N., Wakita, H., Itoh, K., Nishiwaki, K., Suzuki, K., Nagao, R., Yao, H., Hayashi, Y., Satake, S., Hirai, H., Sawada, K-I., Ottmann, O. G., Melo, J. V.
  • Journal Title: Cancer Letter Volume: 312(2) Issue: 2 Pages: 228-34
  • DOI: 10.1016/j.canlet.2011.08.009
  • Peer Reviewed
• [Journal Article] Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells (2011)
  • Author(s): Takeuchi M, Ashihara E, Maekawa T, et al
  • Journal Title: Cancer Sci Volume: 102 Issue: 3 Pages: 591-6
  • DOI: 10.1111/j.1349-7006.2010.01813.x
  • NAID: 10029291246
  • Peer Reviewed
• [Journal Article] Growth inhibition of imatinib-resistant CML cells with the T315 mutation and hypoxia-adaptation by AV65 。Va novel Wnt/υ-catenin signaling inhibitor (2011)
  • Author(s): Nagao, R., Ashihara, E., Kimura, S., Strovel, J. W., Yao, H., Takeuchi, M., Tanaka, R., Hayashi, Y., Hirai, H., Padia, J., Strand, K.
  • Journal Title: Cancer Letter Volume: 312(1) Issue: 1 Pages: 91-100
  • DOI: 10.1016/j.canlet.2011.08.002
  • Peer Reviewed
• [Presentation] 一次知覚神経におけるC/EBPβの発現は炎症性痛覚過敏の成立に関与する (2015)
  • Author(s): 山口陽輔、佐々木美佳、山北俊介、松田愛、志馬伸朗ら
  • Organizer: 第19回日本神経麻酔集中治療学会
  • Place of Presentation: 岐阜
  • Year and Date: 2015-04-10 – 2015-04-11
• [Presentation] 敗血症性ショック患者における感染症予測スコアの有用性について (2015)
  • Author(s): 吉田浩輔、志馬伸朗、他
  • Organizer: 第42回日本集中治療医学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-02-09 – 2015-02-11
• [Presentation] C/EBPβによる造血幹細胞制御 (2015)
  • Author(s): 平位秀世、志馬伸朗、他
  • Organizer: 第19回造血器腫瘍研究会
  • Place of Presentation: 佐賀
  • Year and Date: 2015-01-23 – 2015-01-24
• [Presentation] CCR1-Mediated Formation of Liver Microenvironment for Cancer Metastasis. (2014)
  • Author(s): Hirai H, et al
  • Organizer: The 56th ASH Annual Meeting in San Francisco
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] 血液培養の正しい取り方と解釈 (2014)
  • Author(s): 志馬伸朗
  • Organizer: 第27回日本外科感染症学会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-04
  • Invited
• [Presentation] 感染症科医への敗血症ガイドラインの紹介 (2014)
  • Author(s): 志馬伸朗
  • Organizer: 第57回日本感染症学会中日本地方会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] Nosocomial pediatric bacteremia: a single-institute survey. (2013)
  • Author(s): Shime N, Kosaka T, Nakanishi M, Fujita N
  • Organizer: The 28th. International Congress of Chemotherapy and Infection
  • Place of Presentation: Yokohama
• [Presentation] 転写因子C/EBPbはカンジダ感染後の造血幹細胞・骨髄系前駆細胞の増殖を制御する (2013)
  • Author(s): 田村彰広、平位秀世、佐竹早紀子、志馬伸朗、佐和貞治
  • Organizer: 第87回日本感染症学会
  • Place of Presentation: 横浜
• [Presentation] 好中球分化異常と疾患 (2013)
  • Author(s): 平位秀世
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Antibiotics in the ICU. (2011)
  • Author(s): Shime N
  • Organizer: Society of Critical care Medicine, Multiprofessional Critical Care Review Course in Seoul(招待講演)
  • Place of Presentation: Seoul
• [Presentation] BCR/ABL-Mediated Myeloid Expansion Is Promoted by C/EBPβ, a Regulator of Emergency Granulopoiesis. (2011)
  • Author(s): Hayashi Y et al.
  • Organizer: 53rd ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego, USA
• [Presentation] Involvement of C/EBPβ in BCR/ABL-dependent leukemogenesis. (2011)
  • Author(s): Hayashi Y et al.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] 感染時の好中球造血において転写因子C/EBPbetaは造血幹細胞・前駆細胞を含む未分化細胞集団の増幅に関与する
  • Author(s): 佐竹早紀子、平位秀世、志馬伸朗ら
  • Organizer: 第86回日本感染症学会
  • Place of Presentation: 長崎
• [Presentation] Defective mesenchymal stem cells contribute to impaired B cell lymphopoiesis in C/EBPb knockout mice.
  • Author(s): Yoshioka S， Miura Y， Yao H， Hayashi Y，Satake S， Hishita T， Hirai H, et al，
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: KYOTO
• [Book] Gas Biology Research in Clinical Practice (2011)
  • Author(s): Shime N, et al. （分担執筆）
  • Total Pages: 148
  • Publisher: Krager