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

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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.