Role of PPARgamma in the regulation of renin gene expression: from molecule to organism

PPARγ 在肾素基因表达调节中的作用：从分子到生物体

• 批准号: 210362562
• 负责人: Professor Dr. Vladimir Todorov
• 金额: --
• 依托单位: Lehrstuhl für Physiologie und Pathophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/210362562?language=en
• 关键词: Role; PPARgamma; regulation; renin; gene

This project aims to investigate the role of nuclear receptor PPARgamma in the transcriptional control of the renin gene. We have described that PPARgamma is involved in the regulation of renin expression and that the human renin gene has a unique PPARgamma binding sequence termed Pal3. The Pal3 motif mediates a stronger transactivation of the human renin gene in comparison with the mouse renin gene. Therefore the human renin Pal3 site will be further characterized in vitro by studying its transcription factor-binding features as well as the expression pattern of nuclear receptors in native and immortalized clonal renin-producing cells. Next, the role of the Pal3 sequence in the control of the human renin gene expression in vivo will be investigated. To this end, two humanized mouse lines with wild-type or mutated Pal3 will be generated by transgene co-placement. At last, the relevance of PPARgamma for the renin overproduction and the development of arterial hypertension during obesity will be elucidated. For this purpose, mice with PPARgamma deficiency in the reninproducing cells will be used as model. We expect from these experiments novel data regarding the intracellular machinery which controls renin expression. This knowledge is clinically relevant because it will contribute to the overall understanding of the renin-angiotensin-system and thus of the molecular mechanisms of arterial hypertension.

本项目旨在研究核受体PPARGamma在肾素基因转录调控中的作用。我们已经描述了PPARGamma参与肾素表达的调节，并且人类肾素基因有一个独特的PPARGamma结合序列，称为Pal3。与小鼠肾素基因相比，Pal3基序介导了人肾素基因更强的反式激活。因此，通过研究人肾素Pal3的转录因子结合特性以及核受体在天然和永生化的克隆性肾素产生细胞中的表达模式，将在体外进一步鉴定人肾素Pal3位点。接下来，将研究Pal3序列在体内控制人类肾素基因表达中的作用。为此，将通过转基因共置产生两个带有野生型或突变Pal3的人源化小鼠系。最后，PPARGamma与肾素过度产生与肥胖时动脉高血压的发生发展的相关性将被阐明。为此，将以肾素产生细胞中PPARγ缺乏的小鼠为模型。我们期望从这些实验中获得关于控制肾素表达的细胞内机制的新数据。这一知识具有临床意义，因为它将有助于全面了解肾素-血管紧张素系统，从而有助于了解动脉高血压的分子机制。