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2011 Fiscal Year Research-status Report

分子進化工学手法を駆使した毒素中和型アルブミンによるハイブリッド血液浄化法の開発

Research Project

Project/Area Number 23659088
Research InstitutionSojo University

Principal Investigator

小田切 優樹  崇城大学, 薬学部, 教授 (80120145)

Co-Investigator(Kenkyū-buntansha) 丸山 徹  熊本大学, 薬学部, 教授 (90423657)
渡邊 博志  熊本大学, 薬学部, 准教授 (70398220)
Project Period (FY) 2011-04-28 – 2013-03-31
Keywordsアルブミン / 血液浄化法 / 分子進化工学 / 毒性中和 / ハイブリッド
Research Abstract

本研究は、ヒト血清アルブミン(HSA)用に改良したファージ表面提示方法を駆使し、病原毒素に対して優れた結合能を有するHSA変異体(低分子毒素中和(不活性)型、アミロイド中和型)を創製して、前者はアルブミン透析へ、後者はカラム吸着療法へと多角的に応用することで、従来法では除去困難な毒素の体外除去を可能とするハイブリッド血液浄化法の開発を目的として企図された。 病原毒素中和型HSA変異体の作製は、(1)In silicoスクリーニング法と(2)改良型ファージ表面提示法の2段階方式により行う。HSA変異体-リガンド複合体の結晶構造解析データベースに基づくIn silico結合スクリーニング法により、標的病原毒素の結合サイト及び結合残基を予測する。(2)(1)で候補となった結合サイトを鋳型として、HSA変異体作製用に改良したファージ表面提示法を用い、毒素に対してより高い親和性を有するHSA変異体を作製する。回収したファージの提示するHSA変異体の配列をシーケンス解析により同定した。得られた変異体から各種毒素に対して高い親和性を有する変異体を高純度に精製する。 次いで、BR結合活性が有意に高かったドメインII変異体であるpan3_3-13を用い、胆管結紮による高BR血症マウスにてBR除去効果を評価した。血中BR減少効果を比較したところ、pan3_3-13>WTドメインII>saline投与群の順であり、他方、BRの尿中排泄量は、saline<WTドメインII<pan3_3-13投与群の順に増加していた。 今回作製した新規BR尿中排泄促進剤pan3_3-13は、侵襲性の低い新たな血液浄化方法の道を拓くものと期待される。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

全てが当初の予定通りには進んでないものの、変異体の設計と精製法については、ほぼ確立でき、本研究の中核をなすファージディスプレイ法がきわめて有効な方法であることが確かめられ、あらtな血液浄化法の開発も夢ではない。

Strategy for Future Research Activity

ファージディズプレイ法を駆使してより毒素に結合親和力の変異体を見出し、従来除去困難と言われる毒素に対し、侵襲性の低い新たな血液浄化法の開発を目指す。

Expenditure Plans for the Next FY Research Funding

当初の計画で購入を予定していたカラムの試薬等が研究室で在庫しているものでなんとか間に合ったが、変異体の作成、in vitro、in vivo評価などの実験に、平成24年度予定されている予算を執行できると確信している。

  • Research Products

    (39 results)

All 2012 2011

All Journal Article (23 results) (of which Peer Reviewed: 23 results) Presentation (15 results) Book (1 results)

  • [Journal Article] Characterization of the hepatic cellular uptake of α(1) -acid glycoprotein (AGP), part 1: A peptide moiety of human AGP is recognized by the hemoglobin β-chain on mouse liver parenchymal cells.2012

    • Author(s)
      Nishi K, Komori H, Kikuchi M, Uehara N, Fukunaga N, Matsumoto K, Watanabe H, Nakajou K, Misumi S, Suenaga A, Maruyama T, Otagiri M.
    • Journal Title

      J Pharm Sci.

      Volume: 101 Pages: 1599-606

    • Peer Reviewed
  • [Journal Article] Characterization of hepatic cellular uptake of α1-acid glycoprotein (AGP), part 2: Involvement of hemoglobin β-chain on plasma membranes in the uptake of human AGP by liver parenchymal cells.2012

    • Author(s)
      Komori H, Nishi K, Uehara N, Watanabe H, Shuto T, Suenaga A, Maruyama T, Otagiri M.
    • Journal Title

      J Pharm Sci.

      Volume: 101 Pages: 1607-15

    • Peer Reviewed
  • [Journal Article] Quantitative evaluation of the role of cysteine and methionine residues in the antioxidant activity of human serum albumin using recombinant mutants.2012

    • Author(s)
      Iwao Y, Ishima Y, Yamada J, Noguchi T, Kragh-Hansen U, Mera K, Honda D, Suenaga A, Maruyama T, Otagiri M.
    • Journal Title

      IUBMB Life

      Volume: 64 Pages: 450-54

    • Peer Reviewed
  • [Journal Article] Alteration in the pharmacokinetics of hemoglobin-vesicles in a rat model of chronic liver cirrhosis is associated with Kupffer cell phagocyte activity.2011

    • Author(s)
      Taguchi K, Miyasato M, Watanabe H, Sakai H, Tsuchida E, Horinouchi H, Kobayashi K, Maruyama T, Otagiri M
    • Journal Title

      J Pharm Sci.

      Volume: 100 Pages: 775-83

    • Peer Reviewed
  • [Journal Article] Repeated injection of high doses of hemoglobin-encapsulated liposomes (hemoglobin vesicles) induces accelerated blood clearance in a hemorrhagic shock rat model.2011

    • Author(s)
      Taguchi K, Iwao Y, Watanabe H, Kadowaki D, Sakai H, Kobayashi K, Horinouchi H, Maruyama T, Otagiri M.
    • Journal Title

      Drug Metab Dispos.

      Volume: 26 Pages: 2498-502

    • Peer Reviewed
  • [Journal Article] Fluid resuscitation with hemoglobin vesicles prevents Escherichia coli growth via complement activation in a hemorrhagic shock rat model.2011

    • Author(s)
      Taguchi K, Ogaki S, Watanabe H, Kadowaki D, Sakai H, Kobayashi K, Horinouchi H, Maruyama T, Otagiri M.
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 337 Pages: 201-8

    • Peer Reviewed
  • [Journal Article] Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney.2011

    • Author(s)
      Miyamoto Y, Watanabe H, Noguchi T, Kotani S, Nakajima M, Kadowaki D, Otagiri M, Maruyama T.
    • Journal Title

      Nephrol Dial Transplant.

      Volume: 26 Pages: 2498-502

    • Peer Reviewed
  • [Journal Article] Spectroscopic studies of interactions of chondroitin sulfates with cisplatin.2011

    • Author(s)
      Zhang JS, Anraku M, KadowakiD, Imai T, Suenaga A, Odai A, Otagiri M
    • Journal Title

      Carbohydr Res.

      Volume: 346 Pages: 631-637

    • Peer Reviewed
  • [Journal Article] Structural insights into differences in drug-binding selectivity between two forms of human alpha1-acid glycoprotein genetic variants, the A and F1*S forms.2011

    • Author(s)
      Nishi K, Ono T, Nakamura T, Fukunaga N, Izumi M, Watanabe H, Suenaga A, Maruyama T, Yamagata Y, Curry S,Otagiri M
    • Journal Title

      J Biol Chem.

      Volume: 286 Pages: 14427-34

    • Peer Reviewed
  • [Journal Article] An autoantibody against N(ε)-(carboxyethyl)lysine (CEL): possible involvement in the removal of CEL-modified proteins by macrophages.2011

    • Author(s)
      Mera K, Nagai R, Takeo K, Izumi M, Maruyama T, Otagiri M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 407 Pages: 420-5

    • Peer Reviewed
  • [Journal Article] Vitamin D receptor activator reduces oxidative stress in hemodialysis patients with secondary hyperparathyroidism.2011

    • Author(s)
      Tanaka M, Tokunaga K, Komaba H, Itoh K, Matsushita K, Watanabe H, Kadowaki D, Maruyama T, Otagiri M, Fukagawa M.
    • Journal Title

      Ther Apher Dial.

      Volume: 15 Pages: 161-8

    • Peer Reviewed
  • [Journal Article] Quantitative analysis of cysteine-34 on the anitioxidative properties of human serum albumin in hemodialysis patients.2011

    • Author(s)
      Anraku M, Takeuchi K, Watanabe H, Kadowaki D, Kitamura K, Tomita K, Kuniyasu A, Suenaga A, Maruyama T, Otagiri M.
    • Journal Title

      J Pharm Sci.

      Volume: 100 Pages: 3968-76

    • Peer Reviewed
  • [Journal Article] Histidine146 of human serum albumin plays a prominent role at the interface of subdomains IA and IIA in allosteric ligand binding.2011

    • Author(s)
      Kaneko K, Chuang VT, Minomo A, Yamasaki K, Bhagavan NV, Maruyama T, Otagiri M
    • Journal Title

      IUBMB Life.

      Volume: 63 Pages: 277-85

    • Peer Reviewed
  • [Journal Article] Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy.2011

    • Author(s)
      Kugimiya T, Jono H, Saito S, Maruyama T, Kadowaki D, Misumi Y, Hoshii Y, Tasaki M, Su Y, Ueda M, Obayashi K, Shono M, Otagiri M, Ando Y.
    • Journal Title

      Lab Invest.

      Volume: 91 Pages: 1219-28

    • Peer Reviewed
  • [Journal Article] Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism.2011

    • Author(s)
      Tanaka M, Tokunaga K, Maruyama T, Otagiri M, Tominaga Y, Itoh K, Matsushita K, Komaba H, Fukagawa M
    • Journal Title

      Ther Apher Dial.

      Volume: 15 Pages: 38-41

    • Peer Reviewed
  • [Journal Article] Human serum albumin-thioredoxin fusion protein with long blood retention property is effective in suppressing lung injury.2011

    • Author(s)
      Furukawa M, Tanaka R, Chuang VT, Ishima Y, Taguchi K, Watanabe H, Maruyama T, Otagiri M.
    • Journal Title

      J Control Release.

      Volume: 154 Pages: 189-95

    • Peer Reviewed
  • [Journal Article] Toxicodynamic evaluation of a cisplatin-chondroitin sulfate complex using a perfused kidney and human proximal tubular cells.2011

    • Author(s)
      Zhang JS, Kadowaki D, Nonoguchi H, Hirata S, Seo H, Imai T, Suenaga A, Giam Chuang VT, Otagiri M.
    • Journal Title

      Ren Fail.

      Volume: 33 Pages: 609-14

    • Peer Reviewed
  • [Journal Article] Cellular uptake mechanisms and responses to NO transferred from mono- and poly-S-nitrosated human serum albumin.2011

    • Author(s)
      Ishima Y, Yoshida F, Kragh-Hansen U, Watanabe K, Katayama N, Nakajou K, Akaike T, Kai T, Maruyama T, Otagiri M.
    • Journal Title

      Free Radic Res.

      Volume: 45 Pages: 1196-206

    • Peer Reviewed
  • [Journal Article] Biological characteristics of two lysines on human serum albumin in the high-affinity binding of 4Z,15Z-bilirubin-IXα revealed by phage display.2011

    • Author(s)
      Minomo A, Ishima Y, Kragh-Hansen U, Chuang VT, Uchida M, Taguchi K, Watanabe H, Maruyama T, Morioka H, Otagiri M.
    • Journal Title

      FEBS J.

      Volume: 278 Pages: 4100-11

    • Peer Reviewed
  • [Journal Article] S-Nitrosated Human Serum Albumin Dimer is not only a Novel Anti-Tumor Drug but also a Potentiator for Anti-Tumor Drugs with Augmented EPR Effects.f2011

    • Author(s)
      Ishima Y, Chen D, Fang J, Maeda H, Minomo A, Kragh-Hansen U, Kai T, Maruyama T, Otagiri M.
    • Journal Title

      Bioconjug Chem.

      Volume: 23 Pages: 264-71

    • Peer Reviewed
  • [Journal Article] New insight into the redox properties of uremic solute indoxyl sulfate as a pro- and anti-oxidant.2011

    • Author(s)
      Miyamoto Y, Watanabe H, Otagiri M, Maruyama T.
    • Journal Title

      Ther Apher Dial.

      Volume: 15 Pages: 129-31

    • Peer Reviewed
  • [Journal Article] Pharmacokinetic properties of hemoglobin vesicles as a substitute for red blood cells.2011

    • Author(s)
      Taguchi K, Maruyama T, Otagiri M.
    • Journal Title

      Drug Metab Rev.

      Volume: 43 Pages: 362-73

    • Peer Reviewed
  • [Journal Article] Update on the pharmacokinetics and redox properties of protein-bound uremic toxins.2011

    • Author(s)
      Watanabe H, Miyamoto Y, Otagiri M,Maruyama T.
    • Journal Title

      J Pharm Sci.

      Volume: 100 Pages: 3682-95

    • Peer Reviewed
  • [Presentation] Quantitative Analysis of Cysteine-34 on the Anitioxidative Properties of Human Serum Albumin and its Physiological Significance in Hemodialysis Patients2011

    • Author(s)
      Makoto Anraku, Masaki Otagiri, et al.
    • Organizer
      Helsinki Drug Research 2011 Congress
    • Place of Presentation
      Helsinki, Finland
    • Year and Date
      2011 – 918-20
  • [Presentation] Albumin Fusion of Thioredoxin: Evaluation of Its Biological Activity for Potential Therapeutic Applications2011

    • Author(s)
      Masaki Otagiri
    • Organizer
      8th Retro metabolism Based Drug Design(招待講演)
    • Place of Presentation
      Graz, Austria
    • Year and Date
      2011 – 63-4
  • [Presentation] Effect of genetically mannosylated-human serum albumin with nitric oxide on hepatic ischemia reperfusion injury2011

    • Author(s)
      Yu Ishima, Masaki Otagiri, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] The uremic solute indoxyl sulfate acts as an antioxidant against superoxide anion radicals under normal-physiological conditions2011

    • Author(s)
      Yohei Miyamoto, Masaki Otagiri, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] Characterization of structure and function of human serum albumin in patients with liver disease2011

    • Author(s)
      Nagumo K, Otagiri M, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] Carbon monoxide binding red blood cells prevent cytochrome p450 degradation in resuscitation after hemorrhagic shock in a rat model2011

    • Author(s)
      Ogaki S, Otagiri M, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] Improved therapeutic effect of thioredoxin by fusing to human serum albumin against ovalbumin-induced lung injury2011

    • Author(s)
      Ryota Tanaka, Masaki Otagiri, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] Acute-phase protein alpha1-acid glycoprotein acquires anti-bacterial activity through S-nitrosylation by a nitric oxide-dependent mechanism2011

    • Author(s)
      Kaori Watanabe, Masaki Otagiri, et al.
    • Organizer
      4th Asia Pacific Regional ISSX Meeting
    • Place of Presentation
      Tainan. Taiwan
    • Year and Date
      2011 – 422-425
  • [Presentation] A peptide moiety of human α1-acid glycoprotein is recognized by the hemoglobin2011

    • Author(s)
      Suenaga T, Otagiri M, et al.
    • Organizer
      Asian Federation for Pharmaceutical Sciences 2011
    • Place of Presentation
      Malaysia, Kuala Lumpur
    • Year and Date
      2011 – 129-12
  • [Presentation] Interaction between p-cresyl sulfate and indoxyl sulfate during body disposition can influence their serum free concentrations in chronic kidney disease2011

    • Author(s)
      Watanabe H, Otagiri M, et al.
    • Organizer
      Asian Federation for Pharmaceutical Sciences 2011
    • Place of Presentation
      Malaysia, Kuala Lumpur
    • Year and Date
      2011 – 129-12
  • [Presentation] Carbon monoxide bound red blood cells prevent alteration of hepatic cytochrome P450 activity after hemorrhagic shock and resuscitation2011

    • Author(s)
      Ogaki S, Otagiri M, et al.
    • Organizer
      Asian Federation for Pharmaceutical Sciences 2011
    • Place of Presentation
      Malaysia, Kuala Lumpur
    • Year and Date
      2011 – 129-12
  • [Presentation] Human serum albumin-thioredoxin fusion protein with long blood retention property is effective in suppressing lung injury2011

    • Author(s)
      Ishima Y, Otagiri M, et al.
    • Organizer
      Asian Federation for Pharmaceutical Sciences 2011
    • Place of Presentation
      Malaysia, Kuala Lumpur
    • Year and Date
      2011 – 129-12
  • [Presentation] Quantitative assessment of cysteinylated human serum albumin using ESI-TOF/MS and its clinical significance in chronic liver disease2011

    • Author(s)
      Nagumo K, Otagiri M, et al.
    • Organizer
      Asian Federation for Pharmaceutical Sciences 2011
    • Place of Presentation
      Malaysia, Kuala Lumpur
    • Year and Date
      2011 – 129-12
  • [Presentation] Genetically engineered mannosylated-human serum albumin as a versatile carrier for liver-selective therapeutics2011

    • Author(s)
      Toru Maruyama, Masaki Otagiri, et al.
    • Organizer
      2011 AAPS Annual Meeting and Exposition
    • Place of Presentation
      Chicago
    • Year and Date
      2011 – 1014-18
  • [Presentation] Involvement of hemoglobin beta-chain on plasma membrane in uptake of human alpha1-acid glycoprotein into liver2011

    • Author(s)
      Hisakazu Komori, Masaki Otagiri, et al.
    • Organizer
      2011 AAPS Annual Meeting and Exposition
    • Place of Presentation
      Chicago
    • Year and Date
      2011 – 1014-18
  • [Book] HUMAN SERUM ALBUMIN2011

    • Author(s)
      Masaki Otagiri (Ed)
    • Total Pages
      300
    • Publisher
      Sojo University Publishing Center

URL: 

Published: 2013-07-10  

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