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Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD)

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Technical Report,01 Sep 2016,31 Aug 2017

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Regents of the University of Colorado, Denver Aurora United States

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This proposal will study novel mTORC1 and 2 signaling pathways that mediate ADPKD and investigate the effects of mTORC1 Raptor knockout, mTORC2 Rictor knockout or combined mTORC1 and 2 knockout on cyst growth and kidney function. The overall hypothesis is that there is increased mTORC1 4E-BP1 and mTORC2 AktSer473, PKC and SGK1 signaling in PKD kidneys and that combined mTORC1 Raptor knockout and mTORC2 Rictor knockout in Pkd1 -- mice will slow cyst growth and improve kidney function more than mTORC1 Raptor knockout or mTORC2 Rictor knockout alone. We have made significant progress in the first year We have characterized 4E-BP1 signaling pathways in PKD kidneys and cells. We have developed Pkd1--, mTORC2 Rictor -- double knockout mice that demonstrate less cysts than Pkd1 -- mice alone. We have 24 mice in an ongoing experiment to compare the therapeutic effect of the mTOR kinase inhibitor Torin-2 that inhibits both mTORC1 and mTORC2 with sirolimus that inhibits mTORC1 on cyst growth and kidney function. We have used FISP-MRI scanning to obtain measurements of kidney and cyst volume in live PKD mice.

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  • Medicine and Medical Research
  • Pharmacology

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