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

最近的实验和临床数据表明，哺乳动物雷帕霉素靶蛋白（mTOR）激酶作为平衡肾小管增殖，肾小管维持和膀胱生成的分子开关。然而，大多数数据来自雷帕霉素对该途径的药理学抑制，使得不可能区分mTOR激活的精确和细胞特异性作用。我们现在已经建立了一套互补的转基因小鼠模型，确定肾小管细胞自主mTOR信号转导事件作为囊肿起始和囊肿进展的介质。引人注目的是，虽然mTORC1的基因缺失延迟了囊肿的发生和进展，但存在mTORC1独立的囊肿形成，这表明多个信号传导途径在囊肿发生和进展中的协同作用。基于这些小鼠模型，我们假设ADPKD的有效药物治疗需要同步或顺序靶向多个信号通路。本研究的总体目标是了解mTORC1依赖性和mTORC1非依赖性信号传导事件调节囊肿发生的精确时间和分子相互作用，以确定ADPKD的新型创新多靶点治疗方法。

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.