| Project/Area Number |
08671257
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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 |
Hematology
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| Research Institution | Department of Internal Medicine, Keio University School of Medicine |
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Principal Investigator |
KIZAKI Masahiro Dept.of Internal Med.Keio Univ.School of Med.Assistant Prof., 医学部, 講師 (20161432)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Yasuo Dept.of Internal Med.Keio Univ.School of Med.Prof., 医学部・内科, 教授 (00110883)
UEYAMA Yoshito Dept.of Patholohy Tokia Univ.School of Med.Associate Prof., 医学部・病理学, 助教授 (30072408)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1997: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Retinoic acid / Retinoic acid receptor / cell differentiation / apoptosis / acute promyelocytic leukemia / 分化 / レチノイン酸耐性 |
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| Research Abstract |
The biological effects of retinoic acid (RA) are mediated by two distinct families of transcription factors : retinoic acid receptors (RARs) and retinoid X receptors (RXRs). and RXRs and RXRs from heterodimers and regulate retinoid-mediated gene expression. We have developed several series of novel synthetic retinoid receptor agonists and antagonists that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. Using these compounds, we demonstrated that the RAR/RXR pathway is more important for differentiation and proliferation of leukemic cells. We also showed the RAR-mediated signaling pathway is important for differentiation and apoptosis of myeloid leukemic cells. Simple activation of RXRs is not sufficient to induce apoptosis of the cells. Furthermore, HL-60 cells transduced with bcl-2 expression vector showed the same differentiationresponse to retinoids as did parental HL-60 cells even though apoptosis was inhibited in these bcl-2 transduced cells, suggesting that differentiation and apoptosis are regulated independently in myeloid leukemic cells. To understand the mechanisms and identify novel approaches to overcome RA-resistance in acute promyelocytic leukemia (APL), we established the first RA-resistant APL cell line (UF-1) and human RA-resistant mouse model in SCID mice. These cell line and animal models may be useful for investigating the biology of myeloid leukemia in vitro and in vivo, as well as for evaluating novel therapeutoc approaches including patients with RA-resistant APL.
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