Accession Number : AD1048468


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


Descriptive Note : Technical Report,01 Sep 2016,31 Aug 2017


Corporate Author : Regents of the University of Colorado, Denver Aurora United States


Personal Author(s) : Edelstein, Charles L


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1048468.pdf


Report Date : 01 Sep 2017


Pagination or Media Count : 15


Abstract : 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.


Descriptors :   kidney diseases , cysts , inhibitors , drugs


Subject Categories : Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE