Notch signaling is an evolutionarily conserved mechanism for regulating cell lineage diversification and stem cell maintenance. Disruption or activation of the pathway can disturb the normal balance of cell maturation leading to loss of “stemness” or to the initiation and progression of cancer. Despite the potential therapeutic value of Notch pathway modulators, the area of targeting Notch stability has not been directly pursued. We have collaborated with Dr. Ethan Lee’s laboratory (Vanderbilt University Medical Center) to reconstitute the turnover of Notch intracellular domain (NICD) in Xenopus egg extracts. Using this system, we will perform a high-throughput unbiased biochemical screen to identify small molecules that modulate the stability of NICD (University of Cincinnati Drug Discovery Center).
These studies will provide 1) a deeper understanding of an aspect of Notch signal transduction that is poorly understood, 2) identification of novel chemical tools to advance our knowledge of Notch signaling requirements during normal development and in human disease, and 3) identification of potential reagents to regulate protein turnover to improve treatment of Notch-dependent human pathologies.