2007 Fiscal Year Final Research Report Summary
Analysis and pathophysiology of dysregulated expression of the Noxl gene using Noxl knockout mice
| Project/Area Number |
17390218
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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 |
Gastroenterology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
ROKUTAN Kazuhito The University of Tokushima, Institute of Health Biosciences, Graduate School, Professor (10230898)
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| Co-Investigator(Kenkyū-buntansha) |
OHTANI Naoko The University of Tokushima, Institute For Genome Research, Associate Professor (50275195)
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| Project Period (FY) |
2005 – 2007
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| Keywords | NADPH oxidase 1 / Nox organizer 1 / Gene-targeted mice / Gastrointestinal mucosa / Innate immunity / Inflammation / Carcinogenesis / tumor necrosis factor-alpha |
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| Research Abstract |
The gastrointestinal epithelium functions as physical and innate immune barriers against commensal or pathogenic microbes. NADPH oxidase 1 (Nox1) highly expressed in the colon are suggested to play a potential role in host defense. The guinea pig cells constitutively express Nox1, p22^<〓>, p67^<〓>, its homolog NOXA1, and Racl. Helicobacter pylori lipopolysaccharide treatment not only increases the Nox1 mRNA to a greater extent but also newly induces expression of the transcript encoding NOXO1, required for the Nox1 activity. Neither of Nox1 nor NOXO1 mRNAs is present in the normal stomach. Using an immunohistochemical technique, we showed that Nox1 and its partner proteins (NOXO1, NOXA1, and p22^<〓> were expressed in intestinal-type adenocarcinomas, diffuse-type adenocarcinomas, and signet-ring cell carcinomas. We also showed that NOXO1, NOXA1, and p22^<〓> as well as Nox1 were predominantly associated with the Golgi apparatus in these cancer cells. At the same time, we found that diffuse-type adenocarcinomas also contained cancer cells having Nox1 and its partner proteins in their nuclei. These results suggest that the Nox1-base oxidase may play an important role in oxygen radical- and inflammation-dependent carcinogenesis in the human stomach. As for Nox1 in colon epithelial cells, we showed that IFN-γ activates transcription of the human Nox1 gene in T84 cells through STAT1 and a GAS element located between -3818 and -3810 by of the Nox1 5'-flank. We cloned the 5' flank of the NOXO1 gene and showed that TNF-alpha up-regulated the NOXO1 gene through an AP-1-binding site (from -561 to -551 bp, AGTAAGTCATG) of the human NOXO1 gene. These results suggest a potential role of the Nox1-based oxidase system in local innate immune and inflammatory response of the stomach and colon. To confirm this hypothesis, we are now analyzing the role of Nox1 using Nox1-IL-10 and Nox2-IL10 double knockout mice.
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Research Products
(48 results)
