| Project/Area Number |
10557015
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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 | 展開研究 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
HAYASHI Norio Tohoku University, Graduate School of Medicine, Professor (00004606)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Masayuki Tohoku University, Graduate School of Medicine, Professor (50166823)
TAKETANI Shigeru Kyoto Institute of Technology, Faculty of Fiber Science, Associate Professor (20121949)
KOBAYASHI Akira Tohoku University, Graduate School of Medicine, Assistant Professor (50292214)
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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 |
¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 1999: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1998: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | Heme / Erythroid cells / Knockout mice / Transgenic mice / 5-アミノレブリン酸合成酵素 / ヘム生合成 / 遺伝子改変マウス / 鉄芽球性貧血 / 鉄代謝 / 環状鉄芽球 / 赤血球分化 / モデル動物 |
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| Research Abstract |
Heme biosynthesis pathway contains a battery of tissue-specific enzymes, including ALAS-E (Alas2). Our purpose is to clarify the pathogenesis of congenital diseases caused by the defective heme synthesis, such as X-linked sideroblastic anemia (XLSA), through generating an ALAS-E knockout line of mice. We generated ALAS-E knockout mouse line through gene targeting experiments. The ALAS-E-deficient mice were embryonic lethal. The cause of the lethality appeared to be the defective primitive hematopoiesis. Chimeric analysis of ALAS-E-null ES cells revealed the presence of sideroblasts that are similar to those observed in human XLSA patients. It was highly expected that the ring sideroblasts were originated from the ALAS-E-null ES cells. We then generated transgenic (TG) mouse lines expressing ALAS-E mutant molecule isolated from the human samples of XLSA patients under the regulation of GATA1-hematopoietic regulatory domain (G1HRD). When G1HRD-ALAS-Emut TG mice were crossed into ALAS-E-null background, severe phenotypes of ALAS-E-null mice were rescued only partially, suggesting that full-activity of ALAS-E is required to fully rescue the knockout phenotype. The results indicate that the ALAS-E mutant molecule is functionally impaired. These results thus demonstrate that close relationship between heme synthesis and erythropoiesis.
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