1998 Fiscal Year Final Research Report Summary
Does the hyperactivity of the autonomic nervous systems stimulate oncogene expression? The role of neural factors of the expression of oncogenes and apoptosis.
| Project/Area Number |
09670562
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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 |
Gastroenterology
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| Research Institution | Yokohama City University |
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Principal Investigator |
KIBA Takayoshi Medical School, Yokohama City University Assistant, 医学部, 助手 (80285139)
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| Co-Investigator(Kenkyū-buntansha) |
SEKIHARA Hisahiko Medical School, Yokohama City University Professor, 医学部, 教授 (80126094)
TANAKA Kastuaki Medical School, Yokohama City University Associate Professor, 医学部, 助教授 (10201617)
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| Project Period (FY) |
1997 – 1998
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| Keywords | apoptosis / oncogene / autonomic nervous system / vagus nerve / liver / Fas / Fas ligand / ventromedial hypothalamus |
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| Research Abstract |
Ventromedial hypothalamic lesions result in increased DNA content in the rat liver. We examined whether this mitotic response involved acinar zones 1, 2 or 3. Changes in immunohistochemical labeling indices in rat liver were measured until 7 days after ventromedial hypothalamic lesioning in rats using an antibody against proliferating cell nuclear antigen. Proliferation of hepatocyte in acinar zones 1-3 began to increase at 1 day, and reached a maximum at 3 days. The most intense proliferation progressively shifted from acinar zone 1 to 3. Increased of proliferation was inhibited completely by hepatic vagotomy. Since cell proliferation and apoptosis play an essential role in the development and homeostasis of the liver, we examined expression of the Fas (APO-1/CD95) and Fas ligand system, which can induce apoptosis in rats with VMH lesions. Northern and Western blotting analysis indicated that VMH lesions lead to a significant increase in Fas mRNA from days 1 to 6 (maximum at day 3), i
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n Fas protein from days 1 to 7 (maximum at day 3), and in Fas ligand mRNA and protein from days 2 to 7 (mRNA : maximum at day 3 ; protein : maximum at day 3 and 4). Immunohistochemistry indicated that the region of strongest Fas expression shifted from acinar zone 1 to zones 2 and 3 by day 5 after VMH lesioning, and that no Fas-positive cells were present in liver tissue at day 0 and 1, but that at days 2-7, many Fas-ligand-positive mononuclear cells were present in the portal veins and central veins, and Fas-ligand-positive cell membranes and cytoplasms of hepatocytes were randomly present in acinar zones 1-3. We also immunohistochemically examined the expression of caspase-3, one of caspases that play a key role in the execution phase of apoptosis. Immunohistochemistry also demonstrated the expression of caspase-3 in the liver after VMH lesioning. In addition, electron microscopy and TUNEL assay showed that VMH lesions mediated apoptosis. Furthermore, the Fas/Fas ligand system induced hepatic cytotoxicity was present. All of these effects were completely inhibited by hepatic vagotomy. Since the cytoplasmic region (death domain) of Fas is well known to be essential for Fas-mediated apoptosis, mutations in this region were investigated by PCR-SSCR analysis up to 12 months after VMH lesioning, but none were detected. We concluded that hepatic vagal hyperactivity produced by VMH lesions stimulates Fas/Fas ligand-mediated apoptosis in rat liver. Less
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