The Role of mTOR dependent and independent signalling pathways for renal tubular cystogenesis

点击翻译按钮获取中文摘要

Recent experimental and clinical data suggest the mammalian target of rapamycin (mTOR) kinase as a molecular switch balancing tubular proliferation, tubular maintenance and cystogenesis. However, most data have been derived from pharmacological inhibition of the pathway by rapamycin making it impossible to differentiate the precise and cell specific role of mTOR activation. We have now established a set of complementary transgenic mouse models that identify tubular cell autonomous mTOR signalling events as mediators of cyst initiation and cyst progression. Strikingly, while genetic deletion of mTORC1 delays the onset and progression of cysts, there is an mTORC1 independent cyst formation suggesting a synergistic action of multiple signalling pathways in cyst initiation and progression. Based on these mouse models we hypothesize that an efficient drug therapy of ADPKD will need to target multiple signalling pathways synchronously or sequentially. The overall goal of this study is to understand the precise timing and the molecular interplay of mTORC1 dependent and mTORC1 independent signalling events regulating cystogenesis to identify a novel and innovative multi-target based treatment approach for ADPKD.