DEPTOR as a target for the treatment of chronic inflammation and angiogenesis-dependent diseases
Inventors: David Briscoe
Invention Types: Therapeutics
Research Areas: Cardiovascular/Cardiology, Immunology
Keywords: Drug DiscoveryFor More Information Contact: Ives, Catherine L.
Dr. David Briscoe’s laboratory has demonstrated that DEPTOR, DEP domain containing mTOR interacting protein, is expressed in microvascular endothelial cells (EC) and functions as an upstream regulator of EC activation and EC-dependent pro-inflammatory responses.
Using a transgenic mouse model in which intracellular DEPTOR expression can be manipulated and sustained, Dr. Briscoe’s lab showed that DEPTOR functions in a similar manner in T-cells. By forcing expression of DEPTOR, they observed that T-cells remained quiescent and effector function was not achieved. The group has recently published proof-of-concept of targeting DEPTOR for long-term graft survival. They found that induced expression of DEPTOR within CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, and increases survival and suppressive function. In vivo, fully MHC mismatched cardiac allograft survival is significantly prolonged in DEPTOR knock‐in recipients and that prolonged survival is dominantly mediated via induced expression and function of DEPTOR within recipient CD4+ T regulatory cells.
Additionally, Dr. Briscoe’s group discovered that a small molecule inhibitor of a Cullin ligase that controls DEPTOR degradation can also target DEPTOR in T cells and this compound allowed DEPTOR to remain over-expressed in both EC and T cells. This suggests that families of such molecules may serve as a potent anti-inflammatory agent that sustains DEPTOR levels and its regulatory effects on downstream signaling pathways.
• Novel treatment pathway for chronic inflammatory or angiogenesis-dependent disorders
• Target to promote long-term graft survival
• Sponsored research opportunity
Key Publications: • Bruneau S, et al. DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses. Blood. 2013 Sep 5;122(10):1833-42.
• Wedel J, et al. Deptor modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation. Am J Transplant. 2018 Jul 3. https://doi.org/10.1111/ajt.14995
Related Publications: Caron A, Briscoe DM, Richard D, Laplante M. DEPTOR at the Nexus of Cancer, Metabolism, and Immunity. Physiol Rev. 2018 Jul 1;98(3):1765-1803. doi: 10.1152/physrev.00064.2017.
IPStatus: Not applicable