Analyses of gene function for telomere dependent cellular senescence

• Project/Area Number: 24590468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: Ishikawa Naoshi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (30184485)
• Co-Investigator(Renkei-kenkyūsha): NAKAMURA Ken-ichi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (60159069) ; TAKUBO Kaiyo 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 研究員 (00154956)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: テロメア / リプログラミング / ウェルナー症候群 / 加齢 / 線維芽細胞 / 細胞老化 / iPS細胞 / ダウン症 / 細胞系列特異性 / WRN遺伝子 / 染色体不安定化

Outline of Final Research Achievements

We have analyzed the in vivo telomere dynamics in Werner syndrome, trisomy 21, and diabetes. Furthermore, our studies of telomere dynamics in patients after living-donor liver transplantation, and in patients with alcoholism and actinic keratosis, have revealed possible factors impacting on telomere maintenance. We also observed end-to-end chromosome fusion in human fibroblast strains at the senescent stage with very short telomeres, and some tumor cells, suggesting that telomere loss could play a role in genetic instability associated with tumorigenesis.
Recently, we analyzed details of the telomere dynamics in iPS cells, indicating that telomere has been lengthen or well maintained during reprograming process. The telomeres of some iPS cell strains became shorter as passages increased without differentiation induction, and those strains showed chromosomal abnormalities. The data suggested that telomere shortening could be a novel marker of iPS cell quality.

Research Products

• [Int'l Joint Research] Terry Fox Laboratory(Canada)
• [Journal Article] Telomere attrition and restoration in the normal teleost Oryzias latipes are linked to growth rate and telomerase activity at each life stage. (2016)
  • Author(s): Hitoshi Hatakeyama, Hiromi Yamazaki, Ken‐Ichi Nakamura, Naotaka Izumiyama‐Shimomura, Junko Aida, Hiroetsu Suzuki, Shuichi Tsuchida, Masaaki Matsuura, Kaiyo Takubo, and Naoshi Ishikawa.
  • Journal Title: AGING Volume: 8 (1) Pages: 1-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Changes of telomere status with aging: An update (2016)
  • Author(s): Naoshi Ishikawa, Ken-Ichi Nakamura, Naotaka Izumiyama-Shimomura, Junko Aida, Yoko Matsuda, Tomio Arai and Kaiyo Takubo
  • Journal Title: Geriatr Gerontol Int Volume: 16 Pages: 30-42
  • DOI: 10.1111/ggi.12772
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas. (2015)
  • Author(s): 1.Matsuda Y, Ishiwata T, Izumiyama-Shimomura N, Hamayasu H, Fujiwara M, Tomita K, Hiraishi N, Nakamura K, Ishikawa N, Aida J, Takubo K, Arai T.
  • Journal Title: PLoS One Volume: 10
  • DOI: 10.1371/journal.pone.0117575
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Arm-specific telomere dynamics of each individual chromosome in induced pluripotent stem cells revealed by quantitative fluorescence in situ hybridization. (2014)
  • Author(s): Terai M, Izumiyama-Shimomura N, Aida J, Ishikawa N, Kuroiwa M, Arai T, Toyoda M, Nakamura K, Takubo K.
  • Journal Title: Tissue Cell Volume: 46 Pages: 470-476
  • DOI: 10.1016/j.tice.2014.08.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Determination of telomere length by the quantitative fluorescence in situ hybridization (Q-FISH) method. (2014)
  • Author(s): Aida J, Izumiyama-Shimomura N, Nakamura K, Ishikawa N, Terai M, Mztsuda Y, Aida S, Arai T, Takubo K.
  • Journal Title: Am J Anal Chem Volume: 5 Pages: 775-783
  • DOI: 10.4236/ajac.2014.512086
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Beta Cell Telomere Attrition in Diabetes: Inverse Correlation Between HbA1c and Telomere Length. (2014)
  • Author(s): Tamura Y, Izumiyama-Shimomura N, Kimbara Y, Nakamura K, Ishikawa N, Aida J, Chiba Y, Mori S, Arai T, Aizawa T, Araki A, Takubo K, Ito H.
  • Journal Title: J Clinical Endocrinology and Metabolism. Volume: 99 Pages: 2771-2777
  • DOI: 10.1210/jc.2014-1222
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Q-FISH measurement of hepatocyte telomere lengths in donor liver and graft after pediatric living-donor liver transplantation: Donor age affects telomere length sustainability. (2014)
  • Author(s): Kawano Y., Ishikawa N., Aida J., Sanada Y., Izumiyama-Shimomura N., Nakamura K., Poon SSS., Matsumoto K., Mizuta K., Uchida E., Tajiri T., Kawarasaki H., Takubo K.
  • Journal Title: PLoS One Volume: 9 Pages: 1-10
  • DOI: 10.1371/journal.pone.0093749
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. (2014)
  • Author(s): Sanada Y, Kawano Y, Miki A, Aida J, Nakamura K, Izumiyama NS, Ishikawa N, Arai T, Hirata Y, Yamada N, Okada N, Wakiya T, Ihara Y, Urahashi T, Yasuda Y, Takubo K.
  • Journal Title: Transpl Int. Volume: 27 Pages: 383-390
  • DOI: 10.1111/tri.12273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Beta Cell Telomere Attrition in Diabetes: Inverse Correlation Between HbA1c and Telomere Length. (2014)
  • Author(s): Tamura Y, Izumiyama-Shimomura N, Kimbara Y, Nakamura K, Ishikawa N, Aida J, Chiba Y, Mori S, Arai T, Aizawa T, Araki A, Takubo K, Ito H.
  • Journal Title: J Clinical Endocrinology and Metabolism. Volume: in press
  • Peer Reviewed
• [Journal Article] Q-FISH measurement of telomere length in skin with/without sun exposure or actinic keratosis (2014)
  • Author(s): Ikeda H, Aida J, Hatamochi A, Hamasaki Y, Izumiyama-Shimomura N, Nakamura K, Ishikawa N, Poon SS, Fujiwara M, Tomita K, Hiraishi N, Kuroiwa M, Matsuura M, Sanada Y, Kawano Y, Arai T, Takubo K.
  • Journal Title: Human Pathology. Volume: 45 Pages: 473-480
  • Peer Reviewed
• [Journal Article] Telomere lengths at birth in trisomies 18 and 21 measured by Q-FISH (2014)
  • Author(s): Nakamura K, Ishikawa N, Izumiyama N, Aida J, Kuroiwa M, Hiraishi N, Fujiwara M, Nakao A, Kawakami T, Poon SSS, Matsuura M, Sawabe M, Arai T, Takubo T.
  • Journal Title: Gene Volume: 533 Pages: 199-207
  • DOI: 10.1016/j.gene.2013.09.086
  • Peer Reviewed
• [Journal Article] Telomere shortening in the esophagus of Japanese alcoholics: relationships with chromoendoscopic findings, ALDH2 and ADH1B genotypes and smoking history. (2013)
  • Author(s): Aida J, Yokoyama A, Shimomura N, Nakamura K, Ishikawa N, Terai M, Poon S, Matsuura M, Fujiwara M, Sawabe M, Arai T, Takubo K
  • Journal Title: PLoS One Volume: 8 Pages: 1-7
  • DOI: 10.1371/journal.pone.0063860
  • Peer Reviewed
• [Journal Article] Short telomeres and chromosome instability prior to histologic malignant progression and cytogenetic aneuploidy in papillary urothelial neoplasms. (2013)
  • Author(s): Izumiyama-Shimomura N, Nakamura K, Aida J, Ishikawa N, Kuroiwa M, Hiraishi N, Fujiwara M, Ishikawa Y, Inoshita N, Yonese J, Matsuura M, Poon SS, Arai T, Takubo K.
  • Journal Title: Urol Oncol Volume: in press
  • Peer Reviewed
• [Journal Article] Telomere dynamics in the human pituitary gland : robust preservation throughout adult life to centenarian age (2012)
  • Author(s): Ishikawa N, Nakamura K, Izumiyama N, Aida J, Sawabe M, Arai T, Kishimoto H, Fujiwara M, Ishii A, Takubo K.
  • Journal Title: AGE Volume: 34 Pages: 795-804
  • DOI: 10.1007/s11357-011-9280-y
  • Peer Reviewed
• [Journal Article] 加齢の科学再考． (2012)
  • Author(s): 石川直、仲村賢一、下村七生貴、相田順子、田久保海誉
  • Journal Title: 基礎老化研究 Volume: 36 Pages: 55-60
  • NAID: 10031121039
  • Peer Reviewed
• [Presentation] テロメア短縮の2相性（若年期の急速短縮と中高年期の緩徐な短縮）からヒト老化プロセスを再考する (2015)
  • Author(s): 石川直、仲村賢一、泉山七生貴、相田順子、田久保海誉
  • Organizer: 第38回日本基礎老化学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-06-13
• [Presentation] 上皮小体好酸性細胞は老化細胞か (2015)
  • Author(s): 相田順子、泉山七生貴、石川直、直井美穂、富田健一郎、長谷川佳代、藤原睦憲、松田陽子、新井冨生、田久保海誉
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] 膵腺房中心細胞におけるテロメアの短縮と加齢、発癌、組織幹細胞との関連 (2015)
  • Author(s): 松田陽子、泉山七生貴、富田健一郎、平石直己、仲村賢一、石川直、相田順子、田久保海誉、新井冨生
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] 下垂体細胞のテロメアは加齢で短縮するか？－男女別、前葉、後葉別テロメア長の検討－ (2015)
  • Author(s): 平石直己、藤原睦憲、相田順子、泉山七生貴、仲村賢一、石川直、直井美穂、松田陽子、新井冨生、田久保海誉
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] Telomere shortening in precancerous pancreatic lesions. (2014)
  • Author(s): Matsuda Y, Izumiyama-Shimomura N, Nakamura K, Ishikawa N, Aida J, Yoshimura H, Ishiwata T, Arai T, Takubo K．
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] Q-FISH measurement of hepatocyte telomeres in donor & graft after living-donor liver transplantation. (2014)
  • Author(s): Ishikawa N, Izumiyama-Shimomura N, Aida J, Nakamura K, Takubo K.
  • Organizer: 第37回日本基礎老化学会大会
  • Place of Presentation: 愛知、大府
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] Telomere length of iPS cells measured by Q-FISH method. (2014)
  • Author(s): Nakamura K, Hirose N, Shimomura N, Aida J, Ishikawa N, Takubo K.
  • Organizer: 第37回日本基礎老化学会大会
  • Place of Presentation: 愛知、大府
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] 脂肪腫と異型脂肪腫様腫瘍の細胞遺伝学的、染色体の安定性とテロメア長の差異． (2014)
  • Author(s): 仲村賢一、杉浦善弥、泉山七生貴、石川雄一、藤原睦憲、石川直、相田順子、新井冨生、田久保海誉
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 膵臓を構成する細胞系列別のテロメア長のQ-FISH法による解析：加齢および糖尿病病態との相関の検討． (2014)
  • Author(s): 石川直、泉山七生貴、相田順子、仲村賢一、藤原睦憲、新井冨生、田久保海誉
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 口腔粘膜におけるテロメア短縮とアルコール代謝酵素ADH1B、ALDH2の遺伝子型． (2014)
  • Author(s): 相田順子、泉山七生貴、仲村賢一、石川直、杉浦善弥、藤原睦憲、新井冨生、田久保海誉
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Accelerated in vivo and in vitro telomere loss in Werner syndrome (2013)
  • Author(s): Ishikawa N, Nakamura K, Shimomura N, Aida J, Goto M, Ishikawa Y, Matsuura M, Hatamochi A, Takubo K.
  • Organizer: The 20th IAGG World Congress of Gerontology and Geriatrics
  • Place of Presentation: Seoul
• [Presentation] Factors related to shortening of telomeres in esophageal epithelium (2013)
  • Author(s): Aida J, Shimomura N, Nakamura K, Fujiwara M, Ishikawa N, Arai T, and Takubo K.
  • Organizer: The 20th IAGG World Congress of Gerontology and Geriatrics
  • Place of Presentation: Seoul
• [Presentation] Ｑ-ＦＩＳＨ法により測定したテロメア長を指標とした超百歳リンパ球から樹立されたｉＰＳ細胞の評価 (2013)
  • Author(s): 仲村賢一、広瀬信行、下村-泉山七生貴、相田順子、石川直、田久保海誉
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] ｉＰＳ細胞化によるリプログラミング過程でのテロメア動態のＱ-ＦＩＳＨ法による解析 (2013)
  • Author(s): 石川直、仲村賢一、下村-泉山七生貴、相田順子、寺井政憲、豊田雅士、田久保海誉
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] iPS細胞のテロメアは長くなるか、短くなるか？ (2013)
  • Author(s): 寺井政憲、仲村賢一、泉山-下村七生貴、石川直、豊田雅士、相田順子、田久保海誉
  • Organizer: 第２５回高遠分子細胞生物学シンポジウム
  • Place of Presentation: 滋賀
• [Presentation] The telomeres of the parental cells were elongated by establishment iPSCs, but the telomere extension rate differed among the clones. (2013)
  • Author(s): Ishikawa, N., Terai, M., Toyoda, M., Nakamura, K., Shimomura-Izumiyama, N., and Takubo, K.
  • Organizer: CiRA International Symposium 2013 "Raising the Next Generation of Stem Cell Research."
  • Place of Presentation: Kyoto
• [Presentation] Chromosomal instability could be induced by telomere shortening although established iPSCs maintain telomerase activity. (2013)
  • Author(s): Terai, M. Ishikawa, N., Toyoda, M., Aida, J. and Takubo, K.
  • Organizer: CiRA International Symposium 2013 "Raising the Next Generation of Stem Cell Research."
  • Place of Presentation: Kyoto
• [Presentation] ウェルナー症候群ではin vivo テロメア短縮が亢進している：重回帰解析によりわかったこと． (2012)
  • Author(s): 石川直、仲村賢一、下村七生貴、相田順子、石川雄一、松浦正明、籏持淳、田久保海誉
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ウェルナー症候群患者皮膚テロメア長は正常人群と比べ急速に短縮する －TRFデータの重回帰統計解析－． (2012)
  • Author(s): 石川直、仲村賢一、下村七生貴、相田順子、後藤眞、石川雄一、籏持淳、田久保海誉
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京, 新宿
• [Presentation] Q-FISH法により測定したテロメア長を指標としたiPS細胞の評価. (2012)
  • Author(s): 仲村賢一、豊田雅士、下村-泉山七生貴、相田順子、石川直、櫻井うらら、沢辺元司、新井冨生、田久保海誉
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京, 新宿
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• [Remarks] 高齢者がん研究グループホームページ
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• [Remarks] 高齢者がん研究グループホームページ
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• [Remarks] 高齢者がん研究グループホームページ
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