| Project/Area Number |
10044256
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | YAMANASHI MEDICAL UNIVERSITY |
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Principal Investigator |
MAEDA Shuichiro Yamanashi Med.Univ., Department of Biochemistry, Prof., 医学部, 教授 (10117244)
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| Co-Investigator(Kenkyū-buntansha) |
張 思仲 華西医科大学, 医学遺伝, 教授
SARAIVA M.J. ポルト大学, 分子細胞生物学研究所, 教授
BUXBAUM J.N. ニューヨーク大学, 医学部, 教授
COSTANTINI F コロンビア大学, 医学部, 教授
GOTTESMAN M. コロンビア大学, 癌研究所, 所長
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | Amyloidosis / Transthyretin / Mouse model of disorder / Serum amyloid P component / Gene targeting / Embryonic stem cell / Familial amyloidotic polyneuropathy / Transgenic mouse |
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| Research Abstract |
1) Using the serum amyloid P component (SAP)-deficient mice, we showed that SAP significantly promotes the amyloid deposition. Thus, SAP may play an important role in the pathogenesis of human amyloidoses. However, no enhancement in the rate of regression of splenic AA amyloid was observed in the SAP-deficient mice relative to wild-type mice. These results suggest that dissociation of bound SAP from AA amyloid deposits would not significantly accelerate regression of the deposits in vivo.
2) To assess the ultrastructure of in situ AA amyloid fibrils, we examined the ultrastructure of splenic AA amyloid fibrils in SAP-deficient and wild-type mice. Ultrastructural analysis by quick-freezing and deep-etching method revealed significant differences in the structure of amyloid fibrils in situ between the two types of mice. The light and electron microscopic immunohistochemical analyses, following trypsin treatment, suggested that AA filaments were on the exterior surface of heparan sulfate p
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roteoglycan (HSPG), and that SAP bound to the most exterior surface of the fibrils.
3) We generated mice carrying a point mutation (Val 30 Met) in the endogenous transthyretin (ttr) gene with the use of a novel gene targeting procedure. We suggest that this procedure may be used to introduce subtle mutations efficiently into most genes in mice. Amyloid deposits were detected in the heart, liver, kidney, stomach, small intestine, large intestine, and spleen in 2 out of 22 to 25 month-old 16 heterozygous mutant mice examined. On the other hand, amyloid deposits were not detected in any of the age-matched 16 homozygous mutant and 5 wild-type mice.
4) To elucidate the role of TTR and SAP in the Aβ amyloid deposition, we generated mouse lines carrying a null mutation either at the endogenous ttr or sap locus and human mutant amyloid precursor protein (app) gene, responsible for familial Alzheimer's disease, as a transgene. We are currently examining whether there are any significant differences in the onset progression, and tissue distribution of amyloid deposition between the ttr^<-/-> or sap^<-/-> and control wild-type transgenic mice expressing the human mutant app gene. Less
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