| Project/Area Number |
18390224
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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 | Jichi Medical University |
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Principal Investigator |
SUGANO Kentaro Jichi Medical University, University of Medicine, Professor (60179116)
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| Co-Investigator(Kenkyū-buntansha) |
MUTOH Hiroyuki Jichi Medical University, School of Medicine, Assistant Professor (50322392)
SATOH Kiichi Jichi Medical University, School of Medicine, Assistant Professor (50275707)
OONISHI Hirohide Jichi Medical University, School of Medicine, Assistant Professor (00313023)
OOSAWA Hiroyuki Jichi Medical University, School of Medicine, Assistant Professor (70260833)
YOSHIZAWA Mitsuyo Jichi Medical University, School of Medicine, Ceinical Assistant (80406074)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,810,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2007: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2006: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | Intestinal Metaplasia / CDX2 / siRNA / Sonic Hedeehor / miRNA / Gastric Cancer / COX2 / トランスジェニックマウス / Math1 |
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| Research Abstract |
We have established and reported a mouse model for studying the molecular mechanisms of intestinal metaplasia by expressing CDX2 aberrantly in parietal cells. With this model, detailed studies in and around the formation of intestinal metaplasia revealed that messenger RNA expressions encoding various intestinal cell marker proteins are mobilized preceding the histological phenotype of intestinal metaplasia. These findings indicated that the conversion of gastric mucosa to intestinal metaplasia was initiated in the cells with "gastric phenotype", supporting our previous observation that CDX2 and other intestinal marker messages were detected in the inflammatory gastric mucosa. During this transitional phase, expression of H, K-ATPase, a marker of parietal cell, decreased in parallel with that of sonic hedgehog (SHH), supporting that SHH may be important in maintaining the gastric unit. In accord with this hypothesis, a group of the investigators in the University of Michigan reported t
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hat hedgehog interacting protein (HIP) artificially expressed in the parietal cells resulted in lowered acid secretion as well as decreased number of parietal cells. However, development of intestinal metaplasia was not described in this model, indicating that diminished expression of SHH is not sufficient to form intestinal metaplasia. Thus, initial plan doing the same experiments was withdrawn. However, we observed a complex interplay between hedgehog signaling and Wnt signaling involving also signaling from interstitial tissues such as BMP-4 during CDX2-mediated alteration of cell fate. Further experiments in this line are under way in our laboratory. As CDX2 plays pivotal role in inducing intestinal metaplasia, we planned to examine whether reversal of fully developed intestinal metaplasia is possible by suppressing CDX2 expression. The first approach was by siRNA-mediated knockdown. We designed five different siRNA and transfect them to CDX2 expressing cell lines. Unfortunately, however, none of the siRNA showed any effects of decreasing CDX2 expressions. Currently we are constructing rentivirus vector system to ensure more abundant and longer expression of siRNA that may be more effective in knocking down the CDX2 expressions. Another approach is to study miRNA expression patterns in the tissues obtained from the mice model to identify key miRNAs regulating the development of intestinal metaplasia. A number of unique changes in the miRNA expression were identified. Confirmation of these alterations of miRNA expression by quantitative RT-PCR and in situ hybridization are ongoing and will be reported soon. Less
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