Gene therapy of chronic liver injury with RNAi vector targeting TGF-beta receptor

RNAi载体靶向TGF-β受体基因治疗慢性肝损伤

• 批准号: 16591364
• 负责人: TAJIRI Takashi
• 金额: $ 2.18万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591364/
• 关键词: RNA interference; liver injury; gene therapy; TGF beta; TGF beta receptor II; TGF-β recepter II

Transforming growth factor beta (TGF-B) receptor II (TGF-BRII), which is essential for TGF-B signaling and is involved in the causation or participates in the pathway of various human disorders, is consequently considered a key target for therapeutics and analysis of the pathophysiology associated with disruption of the TGF-B system. In the liver, TGF-B plays an essential role in hepatocyte apoptosis, growth inhibition, and progression of fibrogenesis. There is a critical need to introduce technology involving the TGF-B system, such as RNA interference (RNAi), which has high potential for in vivo therapeutics and analytical activities. Here, we investigated the effect of short hairpin RNA targeting TGF-BRII, using hepatocyte injury in human and mouse cell lines and liver injury mouse models. We demonstrated that short hairpin RNA targeting TGF-BRII can be used to silence TGF-BRII genes in mouse and human cell lines, and physiologic and morphologic changes in hepatocytes suffering from acute injury are spared by RNAi-mediated gene silencing of the target gene and by suppressing downstream signal transduction. Furthermore, short hairpin RNA targeting TGF-BRII protected mice from life-threatening acute liver failure.

转化生长因子β（TGF-B）受体II（TGF-BRII）是TGF-B信号传导所必需的，并且参与各种人类疾病的病因或参与各种人类疾病的途径，因此被认为是治疗和分析与TGF-B系统破坏相关的病理生理学的关键靶标。在肝脏中，TGF-β在肝细胞凋亡、生长抑制和纤维化进展中起重要作用。迫切需要引入涉及TGF-B系统的技术，例如RNA干扰（RNAi），其具有很高的体内治疗和分析活性潜力。在这里，我们研究了靶向TGF-BRII的短发夹RNA的作用，使用人和小鼠细胞系中的肝细胞损伤和肝损伤小鼠模型。我们证明了靶向TGF-BRII的短发夹RNA可用于沉默小鼠和人细胞系中的TGF-BRII基因，并且通过RNAi介导的靶基因沉默和抑制下游信号转导，免于急性损伤的肝细胞的生理和形态变化。此外，靶向TGF-BRII的短发夹RNA保护小鼠免于危及生命的急性肝衰竭。

项目成果

Sequences of RNA functioning as RNA interference targeting human and mouse transforming growth factor beta1 receptor 2

作为针对人和小鼠转化生长因子β1受体2​​的RNA干扰的RNA序列

• 发表时间: 2004

Sequences of RNA functioning as RNA interference targeting human and mouse transforming growth factor betal receptor 2

作为针对人和小鼠转化生长因子β受体2的RNA干扰的RNA序列

• 发表时间: 2004

Short hairpin RNA modulates transforming growth factor beta signaling in life-threatening liverfailure in mice.

短发夹 RNA 在危及生命的小鼠肝衰竭中调节转化生长因子 β 信号传导。

• 发表时间: 2005
• 期刊: Gastroenterology 129
• 作者: Mizuguchi Y;Yokomuro S;Mishima T;Arima Y;Shimizu T;Kawahigashi Y;Kanda T;Yoshida H;Takizawa T;Tajiri T.
• 通讯作者: Tajiri T.