2010 Fiscal Year Final Research Report
Antifibrotic therapy utilizing VA-liposome-siRNAHSP47
| Project/Area Number |
20249044
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | Sapporo Medical University |
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Principal Investigator |
NIITSU Yoshiro Sapporo Medical University, 分子標的探索講座, 特任教授 (10045502)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Yasushi 札幌医科大学, 医学部, 講師 (80343383)
TAKIMOTO Risyu 札幌医科大学, 医学部, 講師 (10336399)
KATO Jyunji 札幌医科大学, 医学部, 教授 (20244345)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 肝臓学 |
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| Research Abstract |
There is no clinically approved treatment modality for organ fibrosis. The stellate cells which is widely distributed in organs strong vitamin A (VA) are considered to be responsible for this pathological condition. Upon tissue damage, the stellate cells start to proliferate and secrete collagen. Prior to the secretion, heart shocks protein 47 plays a critical role intracellularly in helix formation of collagen.
In this research we intended to inhibit collagen secretion from stellate cells by applying siRNA against HSP47, and indeed confirmed this effect by in vitro transfection experiment. We then constructed a complex which was composed of VA coupled liposome and siRNA HSP47 in it.
By injecting this complex into the tail vein. We were able to successfully demonstrate the significant resolution of extracellular matrix in three different cirrhosis models (DMN,CCl4, BDL) of rats. Further in DMN model(lethal model),significant prolongation of survival (100% survival rate)was attained. In addition, similar antifibrotic effect was observed in chronic pancreatitis model of rat. The mechanism underlying this in vivo effect was proven to be, in addition to the inhibition of collagen secretion from stellate cells by siRNA HSP47, resolution of predepositted collagen by tissue collagenase. Thus, with such significant antifibrotic effect, present approach is considered to be promising for future clinical application.
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