2010 Fiscal Year Final Research Report
Analysis of tissue chronic inflammation in adult lifestyle-related diseases and its clinical application
| Project/Area Number |
21790706
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
FUJIU Katsuhito The University of Tokyo, 医学部附属病院, 特任助教 (30422306)
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| Project Period (FY) |
2009 – 2010
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| Keywords | 転写因子 / 炎症 |
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| Research Abstract |
To analyze the function of transcription factor KLF5 in chronic tissue inflammation, we used the inflammation model of mouse kidney. First, we analyzed the phenotype of haploinsufficiency of KLF5 in unilateral ureteral obstruction model (UUO). Halpoinsufficiency of KLF5 showed reduced infiltration of inflammatory monocyte after UUO. In this model, KLF5 controled transcription factor CEBPa and KLF5 and induced CEBPa cooperatively regulated secretion protein S100A8 and S100A9. S100A8 and S100A9 were effector molecules of KLF5 to recruit inflammatory monocyte into kidney. Moreover, S100A8, S100A9 could induce M1 macrophage activation after UUO. These results indicated KLF5 controlled macrophage polarity in kidney and provoked renal inflammation after renal injury.
Next, we analyzed KLF5-S100A8, S100A9 axis in metabolic syndrome. We found KLF5, S100A8 and S100A9 were up-regulated in adipose tissue of obese mice. S100A8 and S100A9 secreted from adipocyte changed macrophage phenotype into more inflammatory phenotype. From these observations, we concluded S100A8 and S100A9 were newly adipocytokine which could induce inflammation of adipose tissue. To further analysis of S100A8 in adipose tissue in vivo, we generated adipocyte specific S100A8 overexpression transgenic mice using AP2 promoter sequence and we have already several lines of transgenic mice.
We tried to address the clinical application from these results. First we thought to handle S100A8 and S100A9 as new target genes in kidney disease and metabolic syndrome. But we isolated more promising candidate genes in these experiments. However, we had to settle the isolation of these candidate genes within this occasion.
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[Journal Article] Bone Marrow-Derived Cells Contribute to Vascular Inflammation but Do Not Differentiate Into Smooth Muscle Cell Lineages.2010
Author(s)
Iwata, H., Manabe, I., Fujiu, K., Yamamoto, T., Takeda, N., Eguchi, K., Furuya, A., Kuro-o, M., Sata, M., Nagai, R.
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Journal Title
Circulation 122
Pages: 2048-2057
Peer Reviewed
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[Journal Article] Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension.2010
Author(s)
Oishi, Y., Manabe, I., Imai, Y., Hara, K., Horikoshi, M., Fujiu, K., Tanaka, T., Aizawa, T., Kadowaki, T., Nagai, R.
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Journal Title
The FASEB Journal 24
Pages: 1780-1788
Peer Reviewed
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[Journal Article] A nanoparticle system specifically designed to deliver short interfering RNA inhibits tumor growth in vivo.2009
Author(s)
Yagi, N., Manabe, I., Tottori, T., Ishihara, A., Ogata, F., Kim, J.H., Nishimura, S., Fujiu, K., Oishi, Y., Itaka, K., et al.
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Journal Title
Cancer Res 69
Pages: 6531-6538
Peer Reviewed
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