Studies on mechanisms for apoptosis and carcinogenessis, and stam cell transplantation in hereditary liver diseases.
| Project/Area Number |
13470508
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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 |
Human genetics
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| Research Institution | Kumamoto University |
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Principal Investigator |
ENDO Fumio Kumamoto University School of Medicine Department of Pediatrics Professor, 医学部, 教授 (00176801)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Kimitoshi Kumamoto University School of Medicine Department of Hospital Assistant, 医学部附属病院, 助手 (30336234)
INDO Yasuhiro Kumamoto University School of Medicine Department of Hospital Lecturer, 医学部附属病院, 講師 (40244131)
YAMAMOTO Tetsuro Kumamoto University School of Medicine Department of Pediatrics Professor, 大学院・医学研究科, 教授 (60112405)
KATOH Hideki Hamamatsu Medical School Experimental Animal Institute Assistant Professor, 医学部附属動物実験施設, 助教授 (30142053)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2002: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2001: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | liver failure / amino acid metabolism / enzyme defect / cancer / mouse model / apoptosis / 遺伝性疾患 / 肝細胞 / 遺伝子発現 / 遺伝子チップ |
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| Research Abstract |
Hreditary tyrosinemia typelis a genetic disease caused by deficiency of fumarylacetoacetate hydrolase (FAH). The patients show severe visceral injuries. Mice with FAH deficiency are neonatal leathal and this hampered the efforts to elucidate the mechanisms of disease process. The use of Fah-/-Hpd-/- double mutants provided new opportunity for studies on tyrosinemias. The studies using the models revealed essential features of visceral injury in this disease.
(1) We analyzed altered expression of genes after the administration of homogentisate in the double mutants by using gene chips. In thisexperiment gene expression patterns in the livers of double mutants and III mice (HPD-/-) were compared. The RNAs interested were analyzed by real-time quantitative RT-PCR Reduction of expression of metabolic enzymes related to carbohydrate, fatty acids are prominent. These results imply that in the patients with HT1, abnormality of metabolisms and blood coagulation factors are specific events relat
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ed to accumulation of FAA in hepatocytes but not one aspect of general liver damage.
(2) we investigated possibility for the presence of endodermal progenitor cells in the damaged salivary gland. For this experiments we used FAH deficient mice as a donor for cell transplantations. After intrasplenic injection of cells prepared from damaged salivary glands, the donor cells were found the liver. Finally we isolated epithelium like cells which proliferate on type I collagen-coated dishes.
(3) The progenitor cell expresses both a6b1 integrin and cytoplasmic laminin. Neural progenitor marker nestin, hematopoietic stem cell marker CD34, and hepatic oval cell markers such as albumin, afetoprotein (AFP) and cytokeratin 19 are negative in this cell. When the cells were transplanted into the liver via portal vein, cells wereintegrated into hepatic trabecula and produced albumin.
(4) When SGP-1 cells formed clusters on type I collagen-coated dishes, they differentiated into endodermal lineage and two major types of clusters appeared. One consisted of hepatocyte-like cell type (hepatic cluster) and the other consisted of islet-like cell type of the pancreas (pancreatic cluster). The hepatic clusters contained cells positive for AFP and/or albumin, and the cells in the pancreatic clusters are positive for glucagon and/or insulin. These cells aretissue stem cells and able to differentiate into endodermal lineageincluding hepatocyte-like cells and islet-like cells. Less
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Report
(3 results)
Research Products
(18 results)
