膵炎発症とオートファジー-Spink3によるオートファジーの制御機構

• Project Area: Proteolysis in the Regulation of Biological Processes
• Project/Area Number: 21025026
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kumamoto University
• Principal Investigator: 大村谷 昌樹 熊本大学, 大学院・先導機構, 特任助教 (60398229)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥6,600,000 (Direct Cost: ¥6,600,000); Fiscal Year 2010: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2009: ¥3,300,000 (Direct Cost: ¥3,300,000)
• Keywords: EGFR / オートファジー / SPINK1/3 / 急性膵炎 / トリプシノーゲン / Autophagy / mTOR / SPINK1

Research Abstract

膵臓内在性のトリプシンインヒビターSPINK1は構造的に上皮増殖因子EGFと類似しており、我々はSPINK1がEGFRに結合し、活性化(リン酸化)することを報告している。またSpink3 (SPINK1のマウスホモログ)欠損マウスでは出生直後の膵腺房細胞において、特異的に過剰なオートファジーが誘導されることから、分泌されたSPINK1/3がEGFRを介してオートファジーを負に制御している可能性がある。この仮説を検証する目的で、EGFRコンディショナルKOマウスを樹立し、解析を行った。このマウスは正常に出生し、その後の成長も正常であった。EGFR familyにはEGFR以外にもHER2,3,4が存在するが、これらのEGFR family分子の発現量には差が見られなかった。オートファジーの誘導に異常がないかを確認するために、24時間の飢餓を行ったが、野生型と同等にオートファジーが誘導されることが確認された。EGFRの主要は細胞内シグナル経路であるMAPK経路、JAK-STAT経路、PI3K-AKT経路でもEGFR欠損による変化は見られなかった。また急性膵炎惹起刺激を加えたが、オートファジーの誘導には差がなく、急性膵炎の重症度にも差が見られなかった。急性膵炎発症には膵内でトリプシノーゲンからトリプシンへの活性化が重要で、その過程でオートファジーが関わっていることを我々は報告しているが、EGFR欠損状態においてもトリプシン活性化に差が見られなかった。以上の結果から、膵腺房細胞において、EGFRはオートファジーの制御には関与していないことが明らかとなった。

Research Products

• [Journal Article] オートファジーの測定・解析方法 (2011)
  • Author(s): 大村谷昌樹
  • Journal Title: Surgery Frontier Volume: (in press)
• [Journal Article] Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression. (2010)
  • Author(s): Wang J
  • Journal Title: Lab Invest Volume: 90 Pages: 654-64
  • Peer Reviewed
• [Journal Article] Chronic pancreatitis in mice by treatment with choline-deficient ethionine-supplemented diet. (2010)
  • Author(s): Ida S
  • Journal Title: Experimental animals Volume: 59 Pages: 421-9
  • Peer Reviewed
• [Journal Article] Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. (2010)
  • Author(s): Romac JM
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 298
  • Peer Reviewed
• [Journal Article] 膵炎におけるオートファジーの意義 (2010)
  • Author(s): 大村谷昌樹
  • Journal Title: 胆と膵 Volume: 31 Pages: 559-564
• [Journal Article] 急性膵炎発症とオートファジー (2010)
  • Author(s): 大村谷昌樹
  • Journal Title: Medical Science Digest Volume: 36 Pages: 22-5
• [Journal Article] Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression. (2010)
  • Author(s): Wang J
  • Journal Title: Lab Invest (In press)
  • Peer Reviewed
• [Journal Article] Chronic pancreatitis in mice by treatment with choline-deficient ethionine-supplemented diet. (2010)
  • Author(s): Ida S
  • Journal Title: Experimental animals (In press)
  • Peer Reviewed
• [Journal Article] Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. (2010)
  • Author(s): Romac JM
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 298
  • Peer Reviewed
• [Journal Article] 萃炎におけるオートファジー意義 (2010)
  • Author(s): 大村谷昌樹
  • Journal Title: 胆と萃 (In press)
• [Journal Article] 急性萃炎発症とオートファジー (2010)
  • Author(s): 大村谷昌樹
  • Journal Title: Medical Science Digest 36
• [Journal Article] Serine protease inhibitor Kazal type 1 (SPINK1) ; beyond the trypsin inhibitor. (2009)
  • Author(s): Ohmuraya M
  • Journal Title: Current Enzyme Inhibition 5 Pages: 110-116
  • Peer Reviewed
• [Journal Article] Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. (2009)
  • Author(s): Ozaki N
  • Journal Title: Mol Cancer Res 7 Pages: 1572-1581
  • Peer Reviewed
• [Journal Article] Effect of low-molecular weight trypsin inhibitor, nafamostat mesilate, on trypsin activity using the pancreatic acinar cells. (2009)
  • Author(s): Hashimoto D
  • Journal Title: Pancreas 38 Pages: 595-597
  • Peer Reviewed
• [Journal Article] Significance of endothelial molecular markers in the evaluation of the severity of acute pancreatits. (2009)
  • Author(s): Ida S
  • Journal Title: Surgery Today 39 Pages: 314-319
  • Peer Reviewed
• [Journal Article] 膵房細胞内トリプシン活性とプロテアーゼインヒビター (2009)
  • Author(s): 橋本大輔
  • Journal Title: Surgery Frontier 16 Pages: 114-119
• [Journal Article] 膵癌発生の分子機構 (2009)
  • Author(s): 大村谷昌樹
  • Journal Title: 細胞工学 28 Pages: 1280-1283
  • NAID: 40016909519
• [Presentation] Serine protease inhibitor Kazal type 1 activates the mammalian target of rapamycin. (2010)
  • Author(s): Masaki Ohmuraya
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場/大阪
  • Year and Date: 2010-09-30
• [Presentation] Serine protease inhibitor Kazal type 3の発現解析 (2010)
  • Author(s): 大村谷昌樹
  • Organizer: 第24回モロシヌス研究会
  • Place of Presentation: グリーンピア南阿蘇/熊本・阿蘇
  • Year and Date: 2010-09-17
• [Presentation] A mouse line expressing Spink3-driven cre recombinasae. (2010)
  • Author(s): Masaki Ohmuraya
  • Organizer: 42^<nd> Meeting of European Pancreatic Club
  • Place of Presentation: Clarion Hotel Sign/Stockholm/Sweden
  • Year and Date: 2010-07-17
• [Presentation] Pancreatic Acinar cell death pathways in acute pancreatitis. (2010)
  • Author(s): Masaki Ohmuraya
  • Organizer: Joint meeting of the international association of pancreatology and the Japan pancreas society 2010
  • Place of Presentation: 福岡国際会議場/Fukuoka.
  • Year and Date: 2010-07-12
• [Presentation] Autophagy delivers trypsinogen to the lysosome in acute pancreatitis. (2009)
  • Author(s): Masaki Ohmuraya
  • Organizer: 4^<th> Meeting on Asia Mouse Mutagenesis and Resource Association
  • Place of Presentation: 熊本大学
  • Year and Date: 2009-12-17
• [Presentation] Serine protease inhibitor Kazal type 1 induces EGFR activation and cell proliferation of pancreatic cancer cells through the epidermal growth factor receptor. (2009)
  • Author(s): Masaki Ohmuraya
  • Organizer: MEETING REGISTRATION 40^<th> Anniversary Meeting of American Pancreatic Association and Japan Pancreatic Society
  • Place of Presentation: Honolulu,USA.ヒルトンハワイアニヴィレンミ
  • Year and Date: 2009-11-06
• [Presentation] Serine protease inhibitor, Kazal type 1 activates the epidermal growth factor receptor. (2009)
  • Author(s): 大村谷昌樹
  • Organizer: 第68回日本癌学会学術総合
  • Place of Presentation: 横浜パミフィコ横浜
  • Year and Date: 2009-10-03
• [Presentation] Autophagy delivers trypsinogen to the lysosome in acute pancereatitis. (2009)
  • Author(s): Masaki Ohmuraya
  • Organizer: International Autophagy Symposium
  • Place of Presentation: 滋賀・大津プリニスホテル
  • Year and Date: 2009-09-26
• [Presentation] Serine protease inhibitor, Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. (2009)
  • Author(s): Masaki Ohmuraya
  • Organizer: 41^<st> Meeting of European Pancreatic Club
  • Place of Presentation: Szeged, Hungary大学
  • Year and Date: 2009-07-03
• [Remarks]
  • URL: http://sendou.kuma-u.jp/research/ohmuratani.html