Mechanism of regulation of immune response by hypoxia-inducible factors and its therapeutic application to inflammatory diseases

• Project/Area Number: 20591181
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Asahikawa Medical College
• Principal Investigator: MAKINO Yuichi Asahikawa Medical College, 医学部, 講師 (90345033)
• Co-Investigator(Kenkyū-buntansha): KOMURA Keiji 旭川医科大学, 大学病院, 医員 (10396385)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 低酸素 / HIF-1 / 炎症細胞 / 関節炎 / IPAS / マクロファージ / ChREBP

Research Abstract

This study was performed to elucidate the role of hypoxia-inducible factors in regulation of immune cell functions and to develop a novel therapeutic approach for inflammatory diseases by targeting the hypoxia-inducible factors. We demonstrated that the expression of HIF-1α was regulated not only by local oxygen tension but also by glucose level and cytokines. Expressed HIF-1α critically contributed to the regulation of the cellular functions. Inhibition of HIF-1 signals in vivo resulted in amelioration of autoimmune arthritis model in mice, indicating that the hypoxia-inducible factors are possible therapeutic targets for inflammatory diseases.

Research Products

• [Journal Article] Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin : A Possible Role of HIF-1α Expression and Oxygen Metabolism (2011)
  • Author(s): Takiyama Y, Harumi T, Watanabe J, Fujita Y, Honjo J, Shimizu N, Makino Y, Haneda M
  • Journal Title: Diabetes 60 Pages: 981-992
  • NAID: 120004606769
  • Peer Reviewed
• [Journal Article] Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Met formin : A Possible Role of Hypoxia Inducible Factor-1 {alpha} Expression and Oxygen Metabolism. (2011)
  • Author(s): Takiyama Y, Harumi T, Watanabe J, Fujita Y, Honjo J, Shimizu N, Makino Y, Haneda M.
  • Journal Title: Diabetes Volume: 60 Pages: 981-992
  • Peer Reviewed
• [Journal Article] High glucose activates HIF-1-mediated signal transduction via carbohydrate response element binding protein in glomerular mesangial cells (2010)
  • Author(s): Isoe T, Makino Y, Mizumoto K, Sakagami H, Fujita Y, Honjo J, Takiyama Y, Itoh H, Haneda M.
  • Journal Title: Kideny Int. 78 Pages: 48-59
  • Peer Reviewed
• [Journal Article] High glucose activates HIF-1-mediated signal transduction in glomer ular mesangial cells through a carbohydrate response element binding protein. (2010)
  • Author(s): lsoe T, Makino_Y, Mizumoto K, Sakagami H, Fulita Y, Honjo J,Takiyama Y, ltoh H, Hane da M
  • Journal Title: Kidney Int Volume: 78 Pages: 48-59
  • Peer Reviewed
• [Journal Article] 転写因子と糖尿病性腎症 (2009)
  • Author(s): 牧野雄一、羽田勝計
  • Journal Title: 月刊糖尿病 1 Pages: 50-58
• [Journal Article] 高血糖による遺伝子発現異常と腎障害 (2009)
  • Author(s): 牧野雄一、磯江つばさ、羽田勝計
  • Journal Title: アンチ・エイジング医学-日本抗加齢医学会雑誌 5 Pages: 196-200
• [Journal Article] 炎症制御における低酸素誘導性転写因子群の役割 (2009)
  • Author(s): 牧野雄一、羽田勝計
  • Journal Title: 外科と代謝・栄養 44 Pages: 225-227
  • NAID: 10026699876
• [Journal Article] Abnormal heart development and lung remodeling in mice lacking a HIF-related bHLH-PAS protein NEPAS (2008)
  • Author(s): Toshiharu Yamashita, Osamu Ohneda, Masumi Nagano, Motoyuki Iemitsu, Yuichi Makino, Hirotoshi Tanaka, Takashi Miyauchi Katsutoshi Goto, Kuniko Ohneda, Yoshiaki Fujii-Kuriyama, Lorenz Poellinger, Masayuki Yamamoto
  • Journal Title: Mol.Cell.Biol. 28 Pages: 1285-1297
  • Peer Reviewed
• [Journal Article] レドックスシグナルと酸化ストレス応答の分子機構を探る (2008)
  • Author(s): 牧野雄一、岡本健作、羽田勝計
  • Journal Title: 分子消化器病 5 Pages: 6-11
• [Journal Article] 低酸素による炎症・免疫制御-HIF-1と炎症・免疫 (2008)
  • Author(s): 牧野雄一羽田勝計
  • Journal Title: 医学のあゆみ 225 Pages: 7203-7207
• [Presentation] 骨格筋のインスリン感受性制御におけるHIF-1αの役割 (2011)
  • Author(s): 坂上英充, 他
  • Organizer: 第8回がんとハイポキシア研究会
  • Place of Presentation: 札幌市
• [Presentation] Role of HIF-1α in regulation of insulin-dependent glucose uptake by Skeletal Muscle Cells (2010)
  • Author(s): Makino Y, et al.
  • Organizer: The 3^<rd> Insulin Resistance in Metabolic Disease Forum
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2010-11-21
• [Presentation] 低酸素応答性転写因子群による遺伝子発現調節機構 (2010)
  • Author(s): 牧野雄一
  • Organizer: 第98回北海道癌談話会例会
  • Place of Presentation: 札幌市
  • Year and Date: 2010-09-19
• [Presentation] 糖尿病性腎症糸球体病変における転写因子HIF-1の活性化 (2010)
  • Author(s): 牧野雄一, 他
  • Organizer: 第3回生活習慣病の転写・シグナルネットワーク研究会
  • Place of Presentation: 鎌倉市
  • Year and Date: 2010-02-20
• [Presentation] Role of hypoxia-independent activation of HIF-1 by high glucose in diabetic glomerulopathy (2010)
  • Author(s): Makino Y, et al
  • Organizer: Keystone symposia, Hypoxia : Molecular mechanisms of oxygen sensing and response pathways
  • Place of Presentation: Keystone, USA
• [Presentation] 骨格筋におけるHIF-1αを介したインスリン感受性制御機構 (2010)
  • Author(s): 坂上英充, 他
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
• [Presentation] The Glucose-Responsive Transcription Factor ChREBP Activates HIF-1-Mediated Gene Expression in Glomerular Mesangial Cells (2010)
  • Author(s): Makino Y, et al
  • Organizer: American Diabetes Association 70^<th> Scientific Sessions
  • Place of Presentation: Orlando, USA
• [Presentation] Knockdown of hypoxia-inducible factor-1 alpha ameliorates insulin-stimulated glucose uptake in the skeletal muscle cells (2010)
  • Author(s): Sakagami H, et al
  • Organizer: 46^<th> EASD meeting
  • Place of Presentation: Stockholm, Sweden
• [Presentation] 低酸素応答性転写因子による生体機能調節機構 (2009)
  • Author(s): 牧野雄一
  • Organizer: 日本生化学会北海道支部・日本生物物理学会北海道支部・北海道分子生物研究会 2009年度合同シンポジウム
  • Place of Presentation: 札幌市
  • Year and Date: 2009-11-13
• [Presentation] 炎症制御における低酸素誘導性転写因子群の役割 (2009)
  • Author(s): 牧野雄一
  • Organizer: 日本外科代謝栄養学会第46回学術集会
  • Place of Presentation: 東京都
  • Year and Date: 2009-07-09
• [Presentation] 血管新生抑制分子IPASによるコラーゲン誘導関節炎の抑制 (2009)
  • Author(s): 牧野雄一, 他
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京都
• [Presentation] 高グルコースは転写因子ChREBPを介してメサンギウム細胞におけるHIFシステムを活性化する (2009)
  • Author(s): 磯江つばさ, 他
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
• [Presentation] High glucose activates hypoxia-inducible factor-mediated signals via carbohydrate response element binding protein in human glomerular mesangial cells (2009)
  • Author(s): Makino Y, et al
  • Organizer: American Diabetes Association 69^<th> Scientific Sessions
  • Place of Presentation: New Orleans, USA
• [Presentation] High glucose activates the hypoxia-inducible factor-1a (HIF-1a)-mediated gene expression in human glomerular mesangial cells. (2009)
  • Author(s): Makino Y, et al
  • Organizer: The 15^<th> Korea-Japan Symposium on Diabetes Mellitus
  • Place of Presentation: Jeju, Kores
• [Presentation] インスリン依存性糖取込みにおけるHIF-1αの役割 (2009)
  • Author(s): 牧野雄一, 他
  • Organizer: 第7回がんとハイポキシア研究会
  • Place of Presentation: 京都市
• [Presentation] 高グルコース下培養メサンギウム細胞ではhypoxia-inducible factor(HIF)が活性化されその標的遺伝子発現が亢進する (2008)
  • Author(s): 磯江つばさ, 他
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京都、東京国際フォーラム
• [Presentation] High Glucose Activates the Hypoxia-inducible Factors (HIFs)-Mediated Signal Transduction in Human Glomerular Mesangial Cells (2008)
  • Author(s): Tsubasa Isoe, et al.
  • Organizer: American Diabetes Association 68^<th> Scientific Sessions
  • Place of Presentation: San Francisco, USA
• [Presentation] Negative feedback regulation of gene expression in hypoxic cells (2008)
  • Author(s): Makino Y.
  • Organizer: The 36th Annual Meeting of International Society on Oxygen Transport to Tissue
  • Place of Presentation: Sapporo, Japan(Invited lecture 7)
• [Presentation] 高グルコースはメサンギウム細胞においてHIF-1を介した転写調節系を作動させる (2008)
  • Author(s): 牧野雄一, 他
  • Organizer: 第23回日本糖尿病合併症学会
  • Place of Presentation: 日本都市センター、東京都
• [Presentation] 高グルコースによるHIFシグナルの活性化 (2008)
  • Author(s): 牧野雄一, 他
  • Organizer: 第6回がんとハイポキシア研究会
  • Place of Presentation: 広島市
• [Book] Hypoxia-inducible factor-1 (HIF-1)の発現制御 からだと酸素の事典 (2009)
  • Author(s): 牧野雄一
  • Publisher: 朝倉書店
• [Remarks] ホームページ等