| Project/Area Number |
15591432
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Iwate medical University School of Medicine |
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Principal Investigator |
SHIDA Kaorul Iwate Med. Univ. School of Med., Dept. of Surg., Assistant Professor, 医学部, 助教授 (70146041)
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| Co-Investigator(Kenkyū-buntansha) |
MAESAWA Chihaya Iwate Med. Univ. School of Med., Dept. of Surg., Assistant Professor, 医学部, 助教授 (10326647)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2003: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Keywords | Stem cell / hTERT / TRE assay / Replicative senescence / Estradiol / Biomolecular ineraction / Telomere / Telomerase / テロメラーゼ / テロメア / ARK / G-quardplex / 分子標的治療薬 / 分子標的治療 / TRE assay / 生体内分子間相互作用解析装置 |
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| Research Abstract |
The telomere is a special cap? like structure at the end of eukaryotic chromosomes, composed of tandem TTAGGG repeats. Telomere length is maintained by a balance between two mechanism: elongation (telomerase) and shortening (end-replication problem) of hexameric repeats. We think that telomerase and telomere structure become potentially important treatment targets for cancer therapy. We have recently developed the telomeric repeat elongation (TRE) assay, a rapid biosensor chip assay using surface plasmon resonance (SPR), for the quantitative assessment of telomerase activity. We have recently focused on the telomerase catalytic subunit (human telomerase reverse transcriptase: hTERT) as a target of telomerase therapy. It is well known that estrogen activates telomerase via a direct effect on the hTERT promoter. In fact, breast cancer cell lines have greater telomerase activity than other types of cancer cell lines. We evaluated the inhibitory effects of tamoxifen (TAM, an anti-estrogen agent), which acts competitively on the estrogen response element (ERE) at the hTERT promoter. TAM decreased the telomerase activity of breast cancer cell lines by approximately 50%, although the down-regulated level was insufficient to achieve cellular senescence or crisis. We have also applied the BIACORE apparatus for screening telomerase inhibitors. The G?quadruplex structure is a suitable target for telomere/telomerase?targeted therapy in the development of a new cancer treatment strategy. To investigate the inhibitory effects of G-quadruplex-mediated telomerase inhibitors, we performed a kinetic assay using the BIACORE apparatus. Rate constants for the interaction of each compound with telomeric DNA were well correlated with the inhibitory effects of telomerase activity evaluated by the TRE assay. Kinetic and TRE assays using SPR technology will be useful for seeking new telomerase inhibitors for molecular target therapy.
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