Targeting Amino Acid-mTORC1 Signaling Limb for TSC Suppression
Abstract
This goal of this project is to define the role of SH3BP4 in TSC development and as a potential therapeutic target for TSC. This annual report provides a complete summary of the research accomplishments to date with respect to the approved statement of work. In the first year of the project, we completed the generation of SH3BP4 flox mice by gene targeting approach. The mice are the unique resource that can be broadly used in many areas of research. The TSC1 flox mice and nestin-Cre mice were also made available. The molecular mechanism studies have been on going to determine the underlying mechanism of SH3BP4 inhibition of Rag GTPases and the smaller fragments of SH3BP4 for the inhibitory function. We determined that NPF motifs are required for the interaction of SH3BP4 with Rag GTPases and mTORC1 inhibition. We identified AP2alpha as a binding protein of SH3BP4 and three candidate proteins. The interaction with other proteins may be important to better understand how SH3BP4 is localized and inhibits Rag GTPases. The brain tumor model system has been well established. We prepared constructs for the brain tumor study and established a quantitative assay method. Furthermore, the brain tissue analysis was conducted and revealed that SH3BP4 is expressed in different levels in different part of the brain, the information critical to develop tissue-specific deletion studies we proposed in specific aim 1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2014
- Accession Number
- ADA602411
Entities
People
- Do-hyung Kim
Organizations
- University of Minnesota