2007 Fiscal Year Final Research Report Summary
Suppression of hepatic ischemia-reperfusion injury by Bad siRNA deliverry
| Project/Area Number |
18590361
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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 |
Experimental pathology
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| Research Institution | Akita University |
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Principal Investigator |
ENOMOTO Katsuhiko Akita University, School of Medicine, Professor (20151988)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIKAWA Yuji Akita University, School of Medicine, Associate Professor (90208166)
OMORI Yasufumi Akita University, School of Medicine, Lecturer (90323138)
YOSHIOKA Toshiaki Akita University, School of Medicine, Assistant Professor (80302264)
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| Project Period (FY) |
2006 – 2007
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| Keywords | liver sinusoidal endothelial cells / apoptosis / Bad siRNA / hepatic ischemic-reperfusion iniury |
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| Research Abstract |
Our previous study revealed that Bad, a proapoptotic protein, plays an important role in apoptosis of hepatic sinusoidal endothelial cells (SEC). Therefore, this study was carried out to establish an appropriate rat model for hepatic ischemia-reperfusion injury (I/R injury) as well as developing methods of the in vivo Bad siRNA delivery to suppress hepatic reperfusion injury.
1) We have established an analytical rat I/R injury model in which the portal veins and hepatic arteries of 2 hepatic lobes were clumped for 90 min and subsequently reperfused. Massive coagulative necrotic lesions appeared in the liver at 3-6 hr after reperfusion and the necrotic lesions were repaired and reorganized by 24 hr. TUNEL staining showed occurrence of a large number of SEC apoptosis within 1 hr after reperfusion but not after 6 hr. The evidence suggests that SEC apoptosis is important for triggering I/R injury of the liver.
2) Before Bad siRNA delivery, we tried injections of the GFP expression plasmid wh
… More
ich was mixed with atelocollagen as carrier matrix through the mesenteric veins, distal portion of portal vein and tail veins. However, no positive signal was detected in both SEC and hepatocytesin the liver. We tried siRNA transfection into the cultured SEC with different carrier matrix, but no efficient suppression of apoptosis was observed so far. Further study on the vivo siRNA delivery method is currently in progress.
3) We have successfully induced fetal SEC maturation in the cultured fetal liver cells of 13.5 embryo with VEGF and SB-431542, an inhibitor of TGF-β1 signaling. Treatment of TGF-β1 induced apoptosis of the cultured SEC from both fetal and adult liver. Thus, we are planning a further study on the effects of TGF-β1 in I/R injury.
In this study, we could establish an appropriate hepatic I/R injury model. Analysis of this model revealed that SEC apoptosis was observed at the very early time after reperfusion and thereafter necrosis of hepatocytes followed, suggesting an initial triggering role of SEC apoptosis in hepatic I/R injury. The method of siRNA delivery to SEC has not yet been established even several different ways of delivery we examined. Studies on fetal liver SEC development, we showed for the first time that TGF-β1 signaling plays a crucial role in SEC apoptosis. Less
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[Journal Article] Osteopontin expression in the liver with severe perisinusoidal fibrosis : Autopsy case of Down syndrome with transient myeloproliferative disorder2008
Author(s)
Tokairin T, Nishikawa Y, Watanabe H, Doi Y, Omori Y, Yoshioka T, Yamamoto Y, Yoshida M, Nishimura T, Li Q, Arai H, Ishida A, Takada G, Enomoto K.
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Journal Title
Pathol. Int. 58
Pages: 64-68
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Maintenance of Bad phosphorylation prevents apoptosis of rat hepatic sinusoidal endothelial cells in vitro and in vivo.2006
Author(s)
Ohi, N, Nishikawa, Y, Tokairin, T, Yamamoto, Y, Doi, Y, et. al.
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Journal Title
Am. J. Pathol. 168
Pages: 1097-1106
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Hyperplasia and carcinomas in Pten-dificient mice and reduced PTEN protein in human bladder cancer patients2006
Author(s)
Tsuruta H, Kishimoto H, Sasaki T, Horie Y, Natsui M, Shibata Y, Hamada K, Yajima N, Kawahara K, Sasaki M, Tsuchiya N, Enomoto K, Mak TW, Nakano T, Habuchi T, Suzuki A.
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Journal Title
Cancer Res. 66
Pages: 8389-8396
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Possible role of the H19 gene in the regulation of hepatocyte proliferation.2007
Author(s)
Nishikawa, Y, Yamamoto, Y, Omori, Y, Yoshioka, T, Yoshida, M, et. al.
Organizer
第66回日本癌学会総会
Place of Presentation
横浜
Year and Date
20071000
Description
「研究成果報告書概要(和文)」より
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[Presentation] P120BP-1, an inducer of epithelial-to-mesenchymal transition, links p120catenin to microtubules.2007
Author(s)
Omori, Y, Nishikawa, Y, Yoshioka, T, Yoshida, M, Enomoto, K.
Organizer
第66回日本癌学会総会
Place of Presentation
横浜
Year and Date
20071000
Description
「研究成果報告書概要(和文)」より
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[Presentation] Roles of the integrin β4 signaling in the prostate cancer progression.2007
Author(s)
Yoshioka, T, Nishikawa, Y, Omori, Y, Yoshida, M, Giancoti, F, et. al.
Organizer
第66回日本癌学会総会
Place of Presentation
横浜
Year and Date
20071000
Description
「研究成果報告書概要(和文)」より
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[Presentation] Cytoplasmic connexin32 enhances motility and metastatic ability of human hepatoma cells in a gap junction-independent manner.2007
Author(s)
Li, Q, Omori, Y, Nishikawa, Y, Yoshioka, T, Yoshida, M, et. al.
Organizer
International Gap Junction Conference 2007.
Place of Presentation
Elsinore, Denmark.
Year and Date
20070800
Description
「研究成果報告書概要(和文)」より
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[Presentation] Cytoplasmic connexin32 enhances growth and metastatic ability of human HuH7 hepatoma cells in vitro and in vivo.2006
Author(s)
Li, Q, Omori, Y, Nishikawa, Y, Yoshioka, T, Yamamoto, Y, et. al.
Organizer
International-Conference Physiological and Pathological Importance of Gap Junction.
Place of Presentation
Tokyo, Japan.
Year and Date
20061100
Description
「研究成果報告書概要(和文)」より
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[Presentation] Sodium orthovanadate inhibits activation of the Rho protein family in cultured hepatic stellate cells.2006
Author(s)
Nishikawa, Y, Ohi, N, Yamamoto, Y, Yoshida, M, Doi, Y, Tokairin, T, et. al.
Organizer
13th International Symposium on Cells of the Hepatic Sinusoid.
Place of Presentation
Nigata, Japan.
Year and Date
20060900
Description
「研究成果報告書概要(和文)」より
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[Presentation] Tumor necrosis factor-α promotes bile duct-like metaplasia of mature rat hepatocytes in vitro.2006
Author(s)
Nishikawa, Y, Omori, Y, Yoshioka, T, Yamamoto, Y, Enomoto, K.
Organizer
FASEB Summer Research Conferences.
Place of Presentation
Colorado, USA.
Year and Date
20060700
Description
「研究成果報告書概要(和文)」より
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[Presentation] Both VEGF and inhibitor of TGF-β1 receptor kinase induce differentiati on of sinusoidal endothelial cells in the culture of fetal rat liver cells.2006
Author(s)
Yoshida, M, Nishikawa, Y, Omori, Y, Yosioka, T, Tokairin, T, et. al.
Organizer
FASEB Summer Research Conferences.
Place of Presentation
Colorado, USA.
Year and Date
20060700
Description
「研究成果報告書概要(和文)」より
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[Presentation] Sodium orthovanadate inhibits activation of the Rho protein family in cultured hepatic stellate cells2006
Author(s)
Nishikawa Y, Ohi N, Yamamoto Y, Yoshida M, Doi Y, Tokairin T, Yoshioka T, OmoriY, Enomoto K.
Organizer
The 13th International Symposium on Cells of the Hepatic Sinusoid,
Place of Presentation
Nigata, Japan.
Year and Date
20060700
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Epithelial-to-mesenchymal transition(EMT)induced by P120BP-1,a newly-identified p120 catenin-binding protein.2006
Author(s)
Omori, Y, Takahashi, Y, Ishizaki, Y, Nishikawa, Y, Yoshioka, T, et. al.
Organizer
The 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress.
Place of Presentation
Kyoto, Japan.
Year and Date
20060600
Description
「研究成果報告書概要(和文)」より
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