Metabolic Regulation of mTORC1 Catalytic Activity
Abstract
The objective of our proposed project is to answer a key basic question that has eluded us and others in the field, but would have direct relevance for future therapeutic strategies for tuberous sclerosis complex (TSC) and cancer patients. mTOR is the drug target of rapamycin-analog therapies used to treat TSC patients, and although successes are reported there are also large groups of unresponsive patients. The current understanding in the field of mTOR research is that mTOR is active in TSC disease due to the loss of its molecular inhibitor (TSC) and that mTOR only works when ATP is highly available. We noticed that in cells that do not have TSC and are forced to lose a lot of their ATP, mTOR is still functional despite suboptimal ATP levels. Therefore, despite many years of study on mTOR and TSC, it is still not understood how mTOR is able to function during nutrient-stress in TSC cells. Our preliminary studies have discovered that molecules from metabolism in the cell can actually promote mTOR and improve its usage of ATP. We believe these findings are important because tumors have large increases in many of these molecules and may therefore be able to increase mTOR function. In our proposed project we intend on thoroughly dissecting how these molecules promote mTOR activation by using biochemistry and molecular biology in TSC-deficient cells. The ultimate applicability of this research once we understand the basic aspects of how mTOR works will be in the future to design novel strategies that reduce or eliminate this mechanism of mTOR activation to one day help TSC and cancer patients. Therefore, the interim outcomes will be to establish the biochemical foundations of this novel finding so that in the future we will be able to rationally design safer and more effective therapies. We envision that our project will advance TSC research and help by contributing scientifically to the fields of mTOR, TSC, and metabolism research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710118
Entities
People
- John Blenis
Organizations
- United States Army
- Weill Cornell Medicine