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Endotoxin binding protein : Novel therapeutic strategy of endotoxin shock.

Research Project

Project/Area Number 08670314
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionIwate Medical University

Principal Investigator

HIRATA Michimasa  Iwate Medical University, Department of Bacteriology, Associate professor., 医学部, 助教授 (20048359)

Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1996: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsLipopolysaccharide(LPS) / Endotoxin-binding protein / Endotoxinneutralization / Synthetic peptides / Antibacterial peptide / Innate immunity / Host defense mechanism / 生体防御
Research Abstract

We purified 18kDa cationic anti-microbial protein (CAP18) with lipopolysaccharide (LPS)-neutralizing activities from rabbit granulocytes. We also cloned a CAP18 family protein from a human bone marrow library. The cloned DNA encoded 140 amino acid residues (CAP181-140). Like the rabbit protein this molecule is comprised of two domains, a highly conserved N-terminal domain of unknown function and a less conserved C-terminal anti-microbial and LPS-neutralizing domain. In the present study, we synthesized new human peptides to identify in more detail the active domain within C-terminal fragment. Synthetic peptide (27 mer, F12-V38) of C-terminal fragment binds to LPS,inhibits LPS-induced activation of Limulus amebocyte lysate, LPS-induced reactive nitrogen release by macrophages and protect mice from LPS lethality. Treatment with the 27 mer peptide also blocked the increase in TNF-alpha levels induced by LPS injection. this peptide also showed antimicrobial activity versus both gram-negative bacteria such as Escerichia coli O157 : H7, salmonella typhimiurium, Klebsiella pneumoniae, Pseudomonas aeruginosa and gram-positive bacteria such as Staphylo-coccus aureus and Streptococcus pneumoniae. Truncation of hydrophobic amino acids from this 27 mer peptide caused a significant decrease in all activities indicating that this 27-mer fragment is the minimal antimicrobial and LPS-neutralizing domain of CAP18.
The amphipathic and alpha-helical structure of this peptide may play a major role in the expression of these activities. The importance of C-terminus hydophobic residues in CAP18 was also suggested. CAP18 and derived peptides may act as host defense protein against infectious diseases, and have therapeutic potential for sepsis and endotoxin shock.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] 平田 陸正: "Systemic inflammatory response syndrome(SIRS):エンドトキシン結合蛋白による制御" Today's Therapy. 20(1). 46 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 平田 陸正: "細菌毒素の毒性発現機序:エンドトキシン." 小児内科. 28(9). 1179-1185 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 平田 陸正: "エンドトキシン結合蛋白によるエンドトキシン活性の制御:エンドトキシン測定上の問題点." 第1回日本エンドトキシン研究会.シンポジウム記録集「エンドトキシン測定法の進歩」. 19-24 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 平田 陸正: "顆粒球由来の生体防御因子:抗菌性ペプチドを中心として" Minophagen Medical Review. 43(1). 1-15 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kirikae T: "Protective effects of a human CAP18-derived peptide against murine endotoxemia" Infect Immun. (In press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Agarwala, K.L., KAwabata, S., Hirata, M., Miyagi, M., Tsunasawa, S., Iwanaga, S.: "A cysteine protease inhibitor stored in the large granules of horseshoe crab hemocytes : Purification, characterization, cDNA cloning and tissue localization" J.Biochem.119(1). 85-94 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawabata, S., Nagayama, R., Hirata, M., Shigenaga, T., Agarwala, K.L., Saito, T., Cho, J., Nakajima, T., Takagi, T., and Iwanaga, S.: "Tachycitin, a small granular component in horseshoe crab hemocytes, is an antimicrobial protein with chitin-binding activity." J.Biochem.120(6). 1253-1260 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawabata, S., Tokunaga, F., Kugi, Y., Motoyama, S., Miura, Y., Hirata, M., Iwanaga, S.: "Limulus factor D,a43-kDa protein isolated from horseshoe crab hemocytes, is a serine protease homologue with antimicrobial activity." FEBS Letter.398. 146-150 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kirikae, T., Hirata, M., Yamasu, H., Kirikae, F., Tamura, H., Kayama, F., Nakatsuka, K.and Nakano, M.: "Protective effects of a human CAP18-derived peptide against murine endotoxemia." Infect. Immun.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Larrick, J.W., Hirata, M., Balint, R.F., Huang, T., Chen, C., Zhong, J and Wright, S.C.: CAP18 : A novel LPS-binding/antimicrobial protein. Novel therapeutic strategies in the treatment of sepsis. Edited by Morrison, D.C and Ryan, J.L.71-91. Marcel Dekker, Inc., (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hirata, M., Wright, S.C., Larrick, J.W: Elsevier Science B.V., (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hirata, M., Wright, S.C., Larrick, J.W: Elsevier Science B.V., (1996)Endotoxin-neutralizing proteins for sepsis and endotoxin shock. Shock, from molecular and cellular level to whole body. Edited by okada, K., Ogata, H., 109-115.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 平田陸正: "顆粒球由来の生体防御因子:抗菌性ペプチドを中心として" Minophagen Medical Review. 43(1). 1-15 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kirikae T: "Protective effects of a human CAP18-derived peptide against murine endotoxemia" Infect Immun. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 平田 陸正(分担): "DIC-その分子病態/診断/臨床スペクトラム/治療" メディカルレビュー社, 490 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 平田 陸正(分担): "エンドトキシン研究シリーズI" 菜根出版(印刷中), (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Agarwala K L: "A cysteine protease inhibitor stored in the large granules of horseshoe crab hemosytes : Purification,characterization ,_cDNA cloning and localization." J.Biochem. 119(1). 85-94 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Larrick J W: "CAP18 : A novel LPS-binding/antimicrobial protein." Novel therapeutic strategies in the treatment of sepsis. 71-91 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirata M: "Endotoxin-neutralizing proteins for sepsis and endotoxin shock." Third International Shock Congress.Symposium "Detection method of lipopolysaccharides and its clinical application". 109-115 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kawabata S: "Limulus factor D,a 43-kDa protein isolated from horseshoe crab hemocytes,is a serine protease homologue with antimicrobial activity." FEBS Letter. 398. 146-150 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平田陸正: "エンドトキシンと結合蛋白" 現代医療. 28(増刊III). 3-11 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平田陸正: "Systemic inflammatory response syndrome (SIRS) エンドトキシンと結合蛋白による制御" Today's Therapy. 20(1). 4-6 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平田陸正: "細菌毒素の毒性発現機序:エンドトキシン." 小児内科. 28(9). 1179-1185 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平田陸正: "エンドトキシン結合蛋白によるエンドトキシン活性の制御:エンドトキシン測定上の問題点" 第1回日本エンドトキシン研究会.シンポジウム記録集「エンドトキシン測定法の進歩」. 19-24 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kawabata S: "Tachycitin,a small granular component in horseshoe crab hemocytes,is an antimicrobial protein with chitin-binding activity." J.Biochem. 120(6). 1253-1260 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平田陸正(分担): "DIC-その分子病態/診断/臨床スペクトラム/治療" メディカルレビュー社, 印刷中 (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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