疾患発症機構の迅速再現系の構築に向けたヒト体細胞遺伝子組み換え法の開発と創薬展開

• Project/Area Number: 19659075
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: 醍醐 弥太郎 The University of Tokyo, 医科学研究所, 准教授 (30345029)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2009: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2008: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2007: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: 遺伝子組み換え / 発癌機構

Research Abstract

本年度はこれまでの研究成果を踏まえ、癌細胞株および癌組織で高頻度に発現上昇する遺伝子として同定した複数個の癌特異的な治療標的候補分子(標的分子)の機能解析を進め、創薬スクリーニングモデル構築に向けた基盤アッセイ系の基礎検討を以下の項目を中心に進めた。
(1)各標的分子をコードする遺伝子を導入した細胞を用いて細胞表現型を観察し、各種発現情報解析による標的分子の下流・関連遺伝子の探索を行った。
(2)HJURP、WDHD1の各分子の組み換え細胞の抽出蛋白を免疫沈降法と質量分析法を併用して解析し、標的分子における癌化に関わる蛋白修飾変動や標的分子と相互作用する蛋白群を同定した。
(3)各種標識された標的分子を発現する細胞株を用いて、標的分子の動態(発現と細胞内局在の変化)およびそれが及ぼす細胞形態変化を観察した。
(4)各標的分子の発現細胞をマウスに移植して、同定した分子経路がin vivoの系で成立するかを確認した。
以上により、新規薬用化合物等のhigh throughput screening系構築に必要な標的分子機能の迅速・高感度検出系の構築を実施した。

Research Products

• [Journal Article] Activation of WD repeat and high-mobility group box DNA binding protein 1 in pulmonary and esophageal carcinogenesis. (2010)
  • Author(s): Sato N, et al.
  • Journal Title: Clin Cancer Res 16 Pages: 226-239
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): 醍醐弥太郎(共著)
  • Journal Title: 分子呼吸器病「呼吸器病学TOPICS2009」(先端医学社) Pages: 50-53
• [Journal Article] HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. (2009)
  • Author(s): Dunleavy EM, et al.
  • Journal Title: Cell 137 Pages: 485-497
  • Peer Reviewed
• [Journal Article] Deficiency of GMDS leads to escape from NK cell-mediated tumor surveillance through modulation of TRAIL signaling. (2009)
  • Author(s): Moriwaki K, et al.
  • Journal Title: Gastroenterology 137 Pages: 188-198
  • Peer Reviewed
• [Journal Article] Activation of placenta specific transcription factor Distal-less homebox 5 predicts chinical outcome in primany lung cancer patients. (2008)
  • Author(s): Kato T, el al.
  • Journal Title: Chin Cancer Res 14 Pages: 2363-2370
  • Peer Reviewed
• [Journal Article] Detection of novel Cancer-Testis antigen-specific T-cell responses in TIL, regional lymph nodes and PBL in patients with esphageal squamous cell carcinoma. (2008)
  • Author(s): Mizukami Y, et al.
  • Journal Title: Cencer Sci 99 Pages: 1448-1454
  • Peer Reviewed
• [Journal Article] TLA-2A-restricted CTL epitopes of a novel lung cancer-associated cancer testis antigen, cell division cycle assosiated 1, can induce tumor-reactive CTL. (2008)
  • Author(s): Leung ACC, et al.
  • Journal Title: Int J Cancer 123 Pages: 2616-2625
  • Peer Reviewed
• [Journal Article] Frequent decreased expression of candidate tumor-suppressor gene, DEC1, and its anchorage-independent growth properties and impact 〓 global gene erpression in esophageal cartinoma. (2008)
  • Author(s): Leung ACC, et al.
  • Journal Title: Int J Cancer 122 Pages: 587-594
  • Peer Reviewed
• [Journal Article] From cancer genomics to thoracic oncology: Discovery of new biomarkers and therapeutic targets for lung and esophageal carcinomas. (2007)
  • Author(s): Daigo Y, et. al.
  • Journal Title: Gen Thorac Cardiovasc Surg 56 Pages: 43-53
  • Peer Reviewed
• [Journal Article] Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. (2007)
  • Author(s): Ishikawa N, et. al.
  • Journal Title: Cancer Res 67 Pages: 11601-11611
  • Peer Reviewed
• [Journal Article] Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells. (2007)
  • Author(s): Kato T, et. al.
  • Journal Title: Cancer Res 67 Pages: 8544-8553
  • Peer Reviewed
• [Journal Article] Molecular features of hormone-refractory prostate cancer cells by genome-wide gene-expression profiles. (2007)
  • Author(s): Tamura K, et. al.
  • Journal Title: Cancer Res 67 Pages: 5117-5125
  • Peer Reviewed
• [Journal Article] Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. (2007)
  • Author(s): Taniwaki M, et. al.
  • Journal Title: Clin Cancer Res 13 Pages: 6624-6631
  • Peer Reviewed
• [Journal Article] Fibroblast Growth Factor Receptor 1 Oncogene Partner as a Novel prognostic biomarker and therapeutic target for lung cancer. (2007)
  • Author(s): Mano Y, et. al.
  • Journal Title: Cancer Sci 98 Pages: 1902-1913
  • Peer Reviewed
• [Journal Article] Identification of HLA-A24-restricted epitope-peptides derived from gene products up-regulated in lung and esophageal cancers as novel targets for immunotherapy. (2007)
  • Author(s): Suda T, et. al.
  • Journal Title: Cancer Sci 98 Pages: 1803-1808
  • Peer Reviewed
• [Journal Article] A novel method for analyzing formalin-fixed paraffin embedded (FFPE) tissue sections by mass spectrometry imaging. (2007)
  • Author(s): Aoki Y, et. al.
  • Journal Title: Proc Jpn Acad, Ser B, Phys Biol Sci 83 Pages: 205-214
  • Peer Reviewed
• [Journal Article] Comparative profiling of serum glycoproteome by sequential purification of glycoproteins and 2-nitrobenzensulfenyl (NBS) stable isotope labeling: a new approach for the novel biomarker discovery for cancer. (2007)
  • Author(s): Ueda K, et. al.
  • Journal Title: J Proteome Res 6 Pages: 3475-3483
  • Peer Reviewed
• [Presentation] Identification of a novel oncogenic receptor tyrosine kinase ELSERT as a new biomarker and a druggable target for lung and esophageal cancer. (2009)
  • Author(s): Yataro Daigo, et al.
  • Organizer: American Association for Cancer Research 100th Annual Meeting
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-21
• [Presentation] がんのゲノミクス・プロテオミクス解析による統合的がん診断系の構築 (2008)
  • Author(s): 醍醐弥太郎
  • Organizer: 日本環境変異原学会第37回大会(シンポジウム)
  • Place of Presentation: 那覇
  • Year and Date: 2008-12-04
• [Presentation] がんゲノム・エピゲノム制御機構に基づいた治療戦略 (2008)
  • Author(s): 醍醐弥太郎
  • Organizer: 日本肺癌学会第49回総会(シンポジウム)
  • Place of Presentation: 小倉
  • Year and Date: 2008-11-13
• [Presentation] Application of Cancer Genomics to Thoracic Oncolgy: New Biomarkers and Druggable Targets for Lung and Esophageal Cancer. (2008)
  • Author(s): Yataro Daigo, et al.
  • Organizer: 日本癌学会第66回総会(International Session)
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] がんプロテオミクス解析による治療標的分子とバイオマーカーの探索 (2008)
  • Author(s): 醍醐弥太郎
  • Organizer: 日本人類遺伝学会第53回大会(シンポジウム)
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-28
• [Presentation] From Cancer Genomics to the Cancer Clinic: Novel Biomarker and Druggable Target Discovery for Lung and Esophageal Cancer. (2008)
  • Author(s): Yataro Daigo, et al.
  • Organizer: 15th East Asian Joint Symposium on Biomedical Science (Symposium)
  • Place of Presentation: Soul, South Korea
  • Year and Date: 2008-07-22
• [Presentation] 網羅的発現解析による肺癌の分子病態理解と新規治療標的分子の探索 (2008)
  • Author(s): 醍醐弥太郎
  • Organizer: 第23回日本肺癌学会ワークショップ(講演)
  • Place of Presentation: 名古屋
  • Year and Date: 2008-07-19
• [Presentation] Phosphorylation and Activation of CDCA8 by AURKB Plays a Significant Role in Human Lung Carcinogenesis. (2007)
  • Author(s): Yataaro Daigo, et. al.
  • Organizer: 日本癌学会第66回総会, International Session
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] Activation of HJURP Involved in the Chromosomal Stability and Immortality of Cancer Cells (2007)
  • Author(s): Yataaro Daigo, et. al.
  • Organizer: 日本癌学会第66回総会, International Session
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Book] THE LUNG perspeetive「肺癌のUp-to-date」 (2008)
  • Author(s): 醍醐弥太郎(共著)
  • Total Pages: 553
  • Publisher: レディカルレビュー社
• [Book] 医学のあゆみ「肺癌update-研究と臨床の最前線」 (2008)
  • Author(s): 醍醐弥太郎(共著)
  • Total Pages: 204
  • Publisher: 医歯薬出版新社
• [Book] MOOK「肺癌の臨床2008-2009」 (2008)
  • Author(s): 醍醐弥太郎(共著)
  • Publisher: 篠原出版新社(印刷中掲載確定)
• [Book] Enzyclopedia of Cancer(掲載確定) (2008)
  • Author(s): Yataro Daigo, et. al.
  • Publisher: Springer(印刷中)
• [Book] 実験医学「分子レベルから迫る癌診断研究」 (2007)
  • Author(s): 醍醐弥太郎(共著)
  • Total Pages: 230
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/nakamura/daigo/cv_daigo.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/nakamura/daigo/main_daigo.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/nakamura/daigo/main_daigo.html