| Project/Area Number |
16590665
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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 |
Circulatory organs internal medicine
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| Research Institution | Niigata University |
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Principal Investigator |
KATO Kiminori Niigata University, Medical and Dental Hospital, Assistant, 医歯学総合病院, 助手 (00303165)
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| Co-Investigator(Kenkyū-buntansha) |
HANAWA Haruo Niigata University, Institute of Medicine and Dentistry, Lecturer, 医歯学系, 講師 (40282983)
KODAMA Makoto Niigata University, Institute of Medicine and Dentistry, Associate Professor, 医歯学系, 助教授 (10242447)
NAKAZAWA Mikio Niigata University, Institute of Medicine and Dentistry, Professor, 医歯学系, 教授 (80143759)
TOBA Ken Niigata University, Medical and Dental Hospital, Lecturer, 医歯学総合病院, 講師 (60313540)
AIZAWA Yoshifusa Niigata University, Institute of Medicine and Dentistry, Professor, 医歯学系, 教授 (50143780)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Keywords | angiogenesis / erythropoietin / erythroblast / CD14 positive cell / CD34 positive cell / VEGF / PLGF |
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| Research Abstract |
A. Clinical trial of bone marrow implantation (BMI) accompanied with erythropoietin (EPO) injection
(1) The results of monotherapy of BMI and combination therapy of BMI and EPO 6,000 IU : EPO injection did not cause major side effects, and no additional effects were observed in the combination therapy compared with the monotherapy. We reported that the number of implanted CD34-positive cells was one of the primary factors that influenced the clinical efficacy of BMI. (Circ J 2004;68:1189-93)
(2) The results of combination therapy of BMI and high dose EPO 24,000IU : Four patients participated. A patient who had been previously treated with the monotherapy one year ago was treated again with the high dose combination therapy. The change of ankle-brachial pressure index revealed the superiority of the high dose combination : monotherapy, 0→0, and the high dose combination, 0→0.67. However, the other 3 patients showed any additional effect of the high dose EPO. Then we tried a combination th
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erapy of BMI and a sequential administration of EPO to obtain prolonged effects of EPO in the ischemic organs.
(3) The results of the combination therapy of BMI and EPO 6,000 IU x 5-days : Four patients participated. One of them showed the improvement of rest pain, but the others did not, and suffered from leg amputation, later. Further device of combination therapy is necessary for such serious patients.
B. Basic research of the mechanism of angiogenesis by erythroblasts and EPO
(1) The additional effect of EPO to BMI (in vivo) : A murine model of limb ischemia was studied. Simultaneous administration of EPO with BMI enhanced angiogenesis by the implanted erythroblasts through further secretion of angiogenic factors by the cells (JMCC 2006:40:629-38).
(2) The facts as stated above (in vitro) : In vitro angiogenesis was performed. Erythroblastic colonies made beforehand from human hematopoietic stem cells produced capillary-like networks around them. The addition of EPO further enhanced the angiogenesis presumably through surviving effects on erythroblasts (JMCC 2006:40:629-38).
(3) The essential role of erythroblast in angiogenesis : Ischemic limbs did not survive in mice transplanted with erythroid-depleted bone marrow cells, hence erythroblasts were essential for the effect in vivo. Limbs did not survive unexpectedly in mice transplanted with purified erythroid cells, and the effects recovered by the simultaneous implantation of CD14-positive bone marrow cells. Therefore the angiogenic effects of BMI arose from the implanted erythroid cells in the presence of the assistance of macrophages (JMCC 2006:40:629-38). Less
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