| Project/Area Number |
16591032
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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 |
Pediatrics
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| Research Institution | Tokai University (2005)
The University of Tokushima (2004) |
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Principal Investigator |
MATSUDA Junko Tokai University, Technology Joint Management Office, Associate Professor, 未来科学技術共同研究センター, 助教授 (60363149)
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| Co-Investigator(Kenkyū-buntansha) |
TOIDA Kazunori Tokushima University, Institute of Health Bioscience, Associate Professor, 大学院・ヘルスバイオサイエンス研究部, 助教授 (40253405)
黒田 泰弘 徳島大学, 副学長 (20035471)
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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: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | sphingolipidosis / lysosomal disease / sphingolipid / saposin D deficient mouse / ceramide / cerebellar Purkinje cell death / model mouse / 神経細胞死抑制効果 |
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| Research Abstract |
Lysosomal storage disorders (LSDs) are a group of over 40 genetic diseases with a combined incidence of about 1:5,000 births. Sphingolipidosis is one of the LSD due to the abnormal metabolism of sphingolipids. Most of the sphingolipidosis show the severe neurological dysfunction. The nervous system is rich in sphingolipids, and their physiological functions in the nervous system are drawing attention in a variety of cellular processes including differentiation, apoptosis and proliferation. Sphingolipid activator proteins (saposins A,B,C,D) are small homologous glycoproteins which are required for in vivo degradation of specific sphingolipids by lysosomal hydrolases. We recently generated a specific saposin A and D deficient mouse by gene targeting technology and found interesting findings to clarify the physiological function of sphingolipids in the nervous system.
We recently generated saposin D knockout mice and found that they showed urinary system defects and cerebellar Purkinje cel
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l (PC) degeneration with accumulation of hydroxy fatty acid-containing ceramide (Matsuda et al. Hum Mol Genet. 2004). In this study, we further investigated the neuropathological phenotype of saposin D^<-/-> mice. Extensive cerebellar PC death is the most prominent feature. As the disease progresses, majority of cerebellar PCs died. In contrast, parvalbumin-immunoreactive GABAergic interneurons and Bergmann's glial cells were well-preserved. The pattern of cerebellar PC death was conspicuous. In the coronal section, the surviving PCs aligned symmetrically in stripes that closely resembled the distribution pattern of Zebrin II and sphingosine kinase probably reflecting the fundamental parasagittal compartmentation of the cerebellum. Furthermore, the number of calbindin-immunoreactive cells was markedly decreased in the cerebral cortex, the amygdala and the hippocampal formation in the terminal stage. Intra-cellular Ca^<2+> homeostasis may play a critical role in ceramide-mediated neuronal cell death. These results provide an insight into the role of ceramide metabolism in the maintenance and function of cerebellar PCs. Less
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