DEVELOPMENT OF THE POSITIVE-FEEDBACK TRANSCRIPTIONAL/REGULATION SYSTEM FOR A DNA VACCINE VECTOR

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE
• Principal Investigator: SASAKI Shin YOKOHAMA CITY UNIV., SCH. OF MED, ASSOCIATE PROFESSOR, 医学部・客員準教授 (40342901)
• Co-Investigator(Kenkyū-buntansha): TAKESHITA Fumihiko YOKOHAMA CITY UNIV., SCH. OF MED, ASSOCIATE PROFESSOR, 医学部, 準教授 (60333572)
• Project Period (FY): 2005 – 2006
• Keywords: DNA VACCINE / TRANSCRUPTION FACTOR / GENE REGULATION

Research Abstract

MAINTAINANCE OF HIGH-LEVEL TRANSGENE EXPRESSION IS THE MAIN CHALLENGE IN CURRENT GENE THERAPY AND GENE-MEDIATED VACCINES. ALTHOUGH THE CYTOMEGALOVIRUS (CMV) PROMOTER/ENHANCER OR ITS DERIVATIVE THE CAG PROMOTER HAS BEEN HARNESSED IN CURRENT GENE THERAPY AND GENE-MEDIATED VACCINE VECTORS, TRANSGENE EXPRESSION BY THESE VECTORS IS OFTEN TRANSIENT AND REMAINS AT SUBOPTIMAL LEVELS DUE TO UNDEFINED MECHANISMS, POSSIBLY INCLUDING THE SHORTAGE OF TRANSCRIPTIONAL MACHINERY. TO OVERCOME THIS DRAWBACK, WE DESIGNED A NOVEL TRANSCRIPTIONAL CONTROL SYSTEM, DESIGNATED HERE AS TRANSCRIPTION FACTOR SUPERCHARGING PROMOTER SYSTEM, IN WHICH TRANSGENE EXPRESSION IS REGULATED BY THE POSITIVE FEEDBACK CIRCUIT CONSISTING OF CIS-AND TRANS-ACTING ELEMENTS OF GENE EXPRESSIONMACHINERY. AMONG COMBINATIOINS OF THESE ELEMENTS, A PLASMID COMPOSED OF A TARGET GENE EXPRESSION CASSETTE DRIVEN BY THE CHIMERIC CMV PROMOTER CONTAINING REPETITIVE 12-0-TETRADECANOYLPHORBOL-13-ACETATE-RESPONSIVE ELEMENTS AS CIS-ACTING ELEMENTS (CMV-TTT) AND EXPRESSION CASSETTES FOR C-FOS AND C-JUN GENES AS TRANS-ACTING ELEMENTS FACILITATED HIGH AND LONG-TERM (>10 MONTHS) EXPRESSION OF A TRANSGENE AFTER IYS INTRAMUSCULAR ELECTROPORATION-MEDIATED DELIVERY IN MICE.. SINCE HUMAN SECRETORY ALKALINE PHOSPHATASE WAS USED AS A REPORTER, IT WAS SUGGESTED THAT THE IMMUNE EVASION MECHANISM ELICITED BY THE CMV-TTT AND/OR C-FOS/C-JUN EXPRESSION ALSO CONTRIBUTED TO THE SUSTAINED EXPRESSION IN MICE.. OUR STRATEGY MAY OPEN A NEW AVENUE FOR A GENE THERAPY THAT INVOLVES LIFELONG SUPPLEMENTATION OF A DEFICIENT PROTEIN THAT COULD BE TARGETED THE HOST' S IMMUNE SYSTEM.

Research Products

• [Journal Article] Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded RNA (dsRNA) in cultured human thyroid follicles. (2007)
  • Author(s): Yamazaki K, Suzuki K, Yamada E, Yamada T, Takeshita F, Matsumoto M, Mitsuhashi T, Obara T, Takano K, Sato K
  • Journal Title: Endocrinology (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Muscle creatine kinase/SV 40 hybrid promoter for muscle-targeted long-term transgene expression (2007)
  • Author(s): Takeshita F, Takase K, Tozuka M, Saha S, Okuda K, Ishii N, Sasaki S
  • Journal Title: Int. J. Mol. Med. 19 Pages: 309-315
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Blocking of the TLR5 activation domain hampers protective potential of DNA vaccine targeting flagellin. (2007)
  • Author(s): Saha S, Takeshita F, Matsuda T, Jounai N, Kobiyama K, Matsumoto T, Sasaki S, Yoshida A, Xin KQ, Klinman DM, Uematsu S, Ishii KJ, Akira S, Okuda K.
  • Journal Title: J.Immunol. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. (2007)
  • Author(s): Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R, Bouvard V, Mansour M, Vincent I, Gissmann L, Iftner T, Sideri M, Stubenrauch F, Tommasino M.
  • Journal Title: J.Immunol. 178 Pages: 3186-3197
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppression of iodide (2007)
  • Author(s): Yamazaki K, Suzuki K, Yamada E, Yamada T, Takeshita F, Matsumoto M, Mitsuhashi T, Obara T, Takano K, Sato K.
  • Journal Title: Endocrinology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Muscle creatine kinase/SV 40 hybrid promoter for muscle-targeted long-term transgene expression. (2007)
  • Author(s): Takeshita F, Takase K, Tozuka M, Saha S, Okuda K, Ishii N, Sasaki S.
  • Journal Title: Int.J.Mol.Med. 19 Pages: 309-315
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A fused gene of nucleoprotein (NP) and herpes simplex virus genes (VP22) induces highly protective immunity against different subtypes of influenza virus (2006)
  • Author(s): Saha S, Yoshida S, Ohba K, Matsui K, Matsuda T, Takeshita F, Umeda K, Tamura Y, Okuda K, Klinman D, Xin KQ, Okuda K
  • Journal Title: Virology 35 Pages: 48-57
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Multivalent DNA vaccine protects mice against pulmonary infection caused by Pseudomonas aeruginosa (2006)
  • Author(s): Saha S, Takeshita F, Sasaki S, Matsuda T, Tanaka T, Tozuka M, Takase K, Matsumoto T, Okuda K, Ishii N, Yamaguchi K, Xin KQ, Klinman DM, Okuda K
  • Journal Title: Vaccine 24 Pages: 6240-6249
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo : An implication for gene therapy targeting congenital protein deficiencies (2006)
  • Author(s): Sasaki S, Smith JM, Takase K, Okuda K, Ishii N, Takeshita F
  • Journal Title: Int. J. Mol. Med. 18 Pages: 289-297
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TLR-adaptor molecules enhance DNA-raised adaptive immune responses against flu and tumor challenge through the activation of innate immunity (2006)
  • Author(s): Takeshita F, Tanaka T, Matsuda T, Tozuka M, Kobiyama K, Saha S, Matsui K, Ishii KJ, Coban C, Akira S, Ishii N, Suzuki K, Klinman DM, Okuda K, Sasaki S
  • Journal Title: J. Virol 80 Pages: 6218-6224
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A fused gene of nucleoprotein (NP) and herpes simplex virus genes (VP22) induces highly protective immunity against different subtypes of influenza virus. (2006)
  • Author(s): Saha S, Yoshida S, Ohba K, Matsui K, Matsuda T, Takeshita F, Umeda K, Tamura Y, Okuda K, Klinman D, Xin KQ, Okuda K.
  • Journal Title: Virology 35 Pages: 48-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Multivalent DNA vaccine protects mice against pulmonary infection caused by Pseudomonas aeruginosa. (2006)
  • Author(s): Saha S, Takeshita F, Sasaki S, Matsuda T, Tanaka T, Tozuka M, Takase K, Matsumoto T, Okuda K, Ishii N, Yamaguchi K, Xin KQ, Klinman DM, Okuda K.
  • Journal Title: Vaccine 24 Pages: 6240-6249
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo : An implication for gene therapy targeting congenital protein deficiencies. (2006)
  • Author(s): Sasaki S, Smith JM, Takase K, Okuda K, Ishii N, Takeshita F.
  • Journal Title: Int.J.Mol.Med. 18 Pages: 289-297
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TLR-adaptor molecules enhance DNA-raised adaptive immune responses against flu and tumor challenge through the activation of innate immunity. (2006)
  • Author(s): Takeshita F, Tanaka T, Matsuda T, Tozuka M, Kobiyama K, Saha S, Matsui K, Ishii KJ, Coban C, Akira S, Ishii N, Suzuki K, Klinman DM, Okuda K, Sasaki S.
  • Journal Title: J.Virol. 80 Pages: 6218-6224
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Double stranded B-DNA activates type-I IFNs gene program via IPS-1/TBK1 pathway. (2006)
  • Author(s): Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Tamamoto M, Uematsu S, Kawai T, Takeuchi 0, Akira S.
  • Journal Title: Nat.Immunol. 7 Pages: 40-48
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hyperproduction of IFN-g by CpG Oligodeoxynucleotide-iduced exacerbation of atopic dermatitis-like skin lesion in some NC/Nga mice. J. (2005)
  • Author(s): Takakura M, Takeshita F, Aihara M, Xin K-Q, Ichino M, Okuda K, Ikezawa Z
  • Journal Title: J.Invest.Dermatol. 125 Pages: 1156-1162
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prime-boost vaccination with plasmid DNA and a chimeric adenovirus type 5 vector with type 35 fiber induces protective immunity against HIV. (2005)
  • Author(s): Xin K-Q, Jounai N, Someya K, Honma K, Mizuguchi H, Naganawa S, Kitamura K, Hayakawa T, Saha S, Takeshita F, Okuda K, Honda M, Klinman DM, Okuda K.
  • Journal Title: Gene Ther. 12 Pages: 1769-1777
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. Eur. (2005)
  • Author(s): Takeshita F, Ishii KJ, Kobiyama K, Kojima Y, Coban C, Sasaki S, Ishii N, Klinman DM, Okuda K, Akira S, Suzuki K.
  • Journal Title: J.Immunol. 35 Pages: 2477-85
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of antigen-specific cellular immune responses between individual PBMCs and splenocytes. (2005)
  • Author(s): Xin K-Q, Ohta S, Jounai N, Takeshita F, Okuda K.
  • Journal Title: Vaccine 23 Pages: 2954-2955
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of novel single stranded RNA that stimulates human CD14+ CD11c+ monocytes. (2005)
  • Author(s): Sugiyama T, Gursel M, Takeshita F, Conover J, Akira S, Klinman DM, Ishii KJ. CpG RNA
  • Journal Title: J.Immunol. 174 Pages: 2273-2279
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7-and TLR9-mediated interferon-alpha induction.
  • Author(s): Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi 0, Akira S.
  • Journal Title: J.Exp.Med. 201 Pages: 915-923
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] 緑膿菌に対して感染防御能を誘導できる医薬組成物 (2004)
  • Inventor(s): 武下文彦
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 特許出願 2006-319535
  • Filing Date: 2004-11-28
  • Description: 「研究成果報告書概要(和文)」より