2007 Fiscal Year Final Research Report Summary
PHYSIOLOGICAL ROLES OF THE CYSTEINE BIOSYNTHETIC PATHWAY AND PATHOSIS INDUCED BY ITS DYSFUNCTION
| Project/Area Number |
18590047
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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 |
Biological pharmacy
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| Research Institution | Gunma University |
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Principal Investigator |
ISHII Isao Gunma University, GRADUATE SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR (90292953)
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| Project Period (FY) |
2006 – 2007
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| Keywords | HOMOCYSTEINE / CYSTEINE / MENTAL RETARDATION / LEARNING AND MEMORY / THROMBOEMBOLISM / CARDIOVASCULAR DISEASES / RISK FACTORS / GENETICALLY-ENGINEERED ANIMALS |
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| Research Abstract |
Cystathionine β-synthase-deficient mice (Cbs-/- ) exhibit several pathophysiological features similar to hyperhomocysteinemic patients, including endothelial dysfunction and hepatic steatosis. Heterozygous mutants (Cbs^<+/-> ) on the C57BL/6J background are extensively analyzed in laboratories worldwide; however, detailed analyses of Cbs^<-/-> have been hampered by the fact that they rarely survive past the weaning age probably due to severe hepatic dysfunction. We backcrossed the mutants with four inbred strains (C57BL/6J(Jcl), BALB/cA, C3H/HeJ, and DBA/2J) for seven generations, and compared Cbs^<-/-> phenotypes among the different genetic backgrounds. Although Cbs^<-/-> on all backgrounds were hyperhomocysteinemic/hypermethioninemic and suffered from lipidosis/hepatic steatosis at 2 weeks of age, >30% of C3H/HeJ-Cbs^<-/-> survived over 8 weeks whereas none of DBA/2J-Cbs^<-/-> survived beyond 5 weeks. At 2 weeks, serum levels of total homocysteine and triglyceride were lowest in C3H/HeJ-Cbs^<-/->. Adult C3H/HeJ-Cbs^<-/-> survivors showed hyperhomocysteinemia but escaped hypermethioninemia, lipidosis, and hepatic steatosis. They appeared normal in general behavioral tests but showed cerebellar malformation and impaired learning ability in the passive avoidance step-through test, and required sufficient dietary supplementation of cyst(e)ine for survival, demonstrating the essential roles of cystathionine b-synthase in the central nervous system function and cysteine biosynthesis. Our C3H/HeJ-Cbs^<-/-> mice could be useful tools for investigating clinical symptoms such as mental retardation and thromboembolism that are found in homocysteinemic patients.
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Research Products
(20 results)
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[Book] 応用栄養学2006
Author(s)
石井 功
Total Pages
383(334-341)
Publisher
第一出版株式会社
Description
「研究成果報告書概要(和文)」より
