Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD)
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2017
- Accession Number
- AD1048468
Entities
People
- Charles L. Edelstein
Organizations
- Regents of the University of Colorado