Brief background of the proposal and its relevance to the CDI’s objectives
Non-alcoholic fatty liver disease (NAFLD) is a common and serious disease characterized by excess liver fat accumulation. NAFLD affects one billion individuals worldwide and is a leading cause of liver failure and transplantation. The most rapidly increasing population acquiring this disease is children, but safe and effective treatments have been lacking. The goal of this project is to identify novel therapies for NAFLD based on targeted inhibition of the sugar transporter, GLUT8. This will be accomplished using a novel drug candidate screen for compounds that have high affinity and selectivity for GLUT8. The hypothesis that selective GLUT8 inhibition reverses fat accumulation in the liver will be examined.
Proposed specific aims
· Identify novel selective small molecule GLUT8 inhibitors.
· Define the safety profile of new and previously identified GLUT8 inhibitors by measuring their effects on glucose metabolism and liver fat accumulation.
· Demonstrate mechanisms by which a candidate GLUT8 inhibitor, “Compound G8i04”, activates
adaptive liver responses.
Potential impact on child health
Identifying selective, high-potency small molecule GLUT8 inhibitors and validating their efficacy against
NAFLD in pre-clinical models will justify full-scale drug development with extension to human clinical trials.