| Project/Area Number |
12670641
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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 | HOKKAIDO UNIVERSITY |
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Principal Investigator |
FUJII Satoshi Hokkaido Univ., Grad. School of Med., Lec., 医学部・附属病院, 講師 (90291228)
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| Co-Investigator(Kenkyū-buntansha) |
IWABUCHII Kazuya Hokkaido Univ., Inst. for Genetic Med., Asso. Prof., 遺伝子病制御研究所, 助教授 (20184898)
ONOE Kazunori Hokkaido Univ., Inst. for Genetic Med., Prof., 遺伝子病制御研究所, 教授 (40002117)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | atherosclerosis / monocyte / macrophage / mouse / bone marrow transplantation / bone marrow chimera / heart transplantation / gene / 骨髄キメラ |
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| Research Abstract |
Atherosclerosis involves complex inflammatory processes between vascular cells and hematocytes in a hyperlipidemic background. Although macrophage specific expression of apolipoprotein (apo) E by bone marrow transplantation (BMT) decreases susceptibility to development of atherosclerosis in apoE deficient (-/-) mice, this method was insufficient for regression of advanced lesions. We hypothesized that atherosclerosis resistant trait potentially present in bone marrow-derived cells can induce regression of advanced lesions. To determine whether cellular manipulation using BMT can favorably affect serum lipoprotein metabolism and induce regression of advanced atheroma, C57BL6/J apoE-/- mice with severe hypercholesterolemia and pre-existing atherosclerotic lesions were irradiated and reconstituted with syngeneic bone marrow cells plus those from wild type (apoE+/+) mice (atherosclerosis susceptible B10.S/SgSlc mice and atherosclerosis resistant SJL/J mice). Stable mixed allogeneic chimera
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mice were established without any detrimental complications. As compared with non-treated apoE-/- mice, partial reconstitution of apoE-/- mice with wild-type marrow cells resulted in a significant reduction of atherogenic non-HDL cholesterol (B10.S 89%, SJL 72% reduction, respectively) and significant regression of the developed lesions 10 weeks after reconstitution, although amounts of serum apoE expressed in these chimeras were less than 1% of those produced in apoE+/+ mice. Furthermore, compared to mixed chimeras reconstituted with atherosclerosis susceptible B10.S bone marrow cells, mixed chimeras reconstituted with atherosclerosis resistant SJL cells resulted in almost complete regression of preexisting atheroma (93% regression, p<0.05 by ANOVA). These results show that resistance to atherosclerosis of SJL mice resides in bone marrow-derived cells independent of serum lipoprotein metabolism and clearance. Mixed allogeneic chimerism is a novel and safe cell-mediated gene therapy for advanced atherosclerosis. Less
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