| Project/Area Number |
16591083
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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 |
Embryonic/Neonatal medicine
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| Research Institution | Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare |
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Principal Investigator |
NAKAJIMA Mitsunari Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, Tokyo Metropolitan Institute of Gerontology, Research Scientist in chief, 東京都老人総合研究所, 主任研究員 (70311404)
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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: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | presenilin 1 / Alzheimer's disease / knockout mice / heart / morphogenesis / congenital heart disease / プレセニリン / 心臓神経堤細胞 |
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| Research Abstract |
Presenilin 1 (PS1) is the gene responsible for the development of early-onset familial Alzheimer's disease. PS1-deficient mice have been reported to show defects in neurogenesis, somitogenesis and angiogenesis. In this project, I found cardiac anomaly in the PS1-deficient mice : The mutant hearts exhibited ventricular septal defect, double outlet right ventricle, and stenosis in the pulmonary artery. Immunohistochemistry using anti-PS1 antibody revealed the prominent expression of PS1 in mesenchymal cells at the septal area of the wild-type heart. These results suggest that PS1 may play an essential role in heart development.
Next, I tried to identify the PS1-expressing cells essential for cardiac development. To achieve the selective disruption of PS1 during development, I prepared a floxed PS1 mice, in which PS1 exons 2 and 3 are flanked by two loxP sites. I also prepared two lines of Cre-recombinase-transgenic mice. In one transgenic line, the Cre recombinase is expressed in neural crest cells under the control of Wnt-1 promoter. In another transgenic line, the enzyme is expressed in endocardial cells under the control of Tie-2 promoter. Cell-type specific expression of the Cre recombinase was confirmed by an X-gal staining of mouse embryos that were prepared by mating cre-recombinase-transgenic mice with CAG-CAT-Z monitor mice. Then I examined the cardiac morphogenesis by serial sections of hearts of conditional knockout mice in which PS1 is lacking in neural crest-derived cells or endocardium-derived cells. Unexpectedly, neither type of conditional knockout mice showed any abnormality in the heart morphology. These results suggest that the heart anomaly in PS1-deficient mice is not induced by the PS1 deficiency in neural crest or endocardium-derived cells.
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