Identification and functional characterization of new components of TOR signalling in C. elegans

哺乳动物雷帕霉素靶蛋白（mTOR）活性的上调与多囊肾病有关，在动物模型和人类中，抑制mTOR途径已被证明可以减小囊肿大小。TOR蛋白复合物1 （T0RC1）在膀胱发生中起着核心作用，但人们对连接纤毛信号和mTOR激活的上游途径知之甚少。在所有高等真核生物中，T0RC1通路在氨基酸和激素依赖信号的响应中促进生长和细胞增殖。在秀丽隐杆线虫中，TORC1的抑制导致发育阻滞，使其发育成类似daer的幼虫，并增加成虫的寿命。我们建立了蛋白质组筛选方法，并确定了Rheb潜在的新相互作用物。初步结果表明，TSC/Rheb不仅控制TORC1信号通路，还可能影响控制细胞周期和增殖的重要信号通路。在这里，我们建议利用秀丽隐杆线虫的强度进行遗传分析，并在遗传水平上表征新发现的调节或影响TORC1信号传导的成分。这一建议将有助于更好地理解TOR信号在发育过程中的复杂性和交叉对话及其在膀胱发生中的作用。

Upregulation of mammalian target of rapamycin (mTOR) activity has been implicated in polycystic kidney disease and inhibition of the mTOR pathway has been shown to decrease cyst size in animal models and humans. The TOR protein complex 1 (T0RC1) has a central role in cystogenesis, but the upstream pathways linking ciliary signalling to mTOR activation are poorly understood. The T0RC1 pathway promotes growth and cell proliferation in response to amino acids and hormone-dependent signalling in all higher eukaryotes. Inhibition of TORC1 in C. elegans results in developmental arrest as dauer-Iike larvae and increases lifespan in the adult worm. We have established proteome-wide screening methods and identified potential new interactors of Rheb. Preliminary results suggest that TSC/Rheb does not only control TORC1 signalling but may also impinge on signalling pathways important for control of cell cycle and proliferation. Here, we propose to employ the strength of C. elegans to perform genetic analyses, and to characterize newly identified components that regulate or effect TORC1 signalling at the genetic level. This proposal will contribute to a better understanding of the complexity and cross-talks of TOR signalling during development and its role in cystogenesis.