The misregulation of Notch signaling has been implicated in developmental defects in many organisms and in human diseases, most notably T-Cell Acute Lymphoblastic Leukemia (T-ALL). This research will characterize the regulation of activated forms of Notch in developmental contexts using Caenorhabditis elegans. Specifically, this research will examine two potentially novel forms of negative regulation that are not understood at the mechanistic level. Both forms of regulation block C. elegans LIN-12/Notch function in the nucleus. In one case, crosstalk with the Ras-MAP kinase pathway blocks the effect of constitutively active LIN-12/Notch specifically where Ras-MAP kinase is activated. In the second case, the novel DNA-binding protein, LIN-14, which regulates developmental timing, blocks constitutively active LIN-12/Notch in a particular tissue. The constitutively active forms o LIN-12 blocked is analogous to mutations found in certain cancers such as T-ALL. In the course of this research, I will characterize the regulation of two required Notch accessory proteins, a well-conserved transcription factor (LAG-1) and a coactivator (SEL-8), and the transcriptional complex they form with LIN-12. Additionally, these methods will be expanded to characterize additional forms of regulation found through manipulation of LIN-12 target reporters. By characterizing these two mechanisms, this proposal aims to increase the understanding of how the critical Notch pathway is regulated and potentially provide novel therapeutic strategies for diseases such as T-ALL.

Public Health Relevance

Several cancers have been linked to over-activation of the signaling pathway Notch. This research will investigate mechanisms by which activated forms of Notch are inhibited from functioning. The findings could lead to new therapeutic strategies for these relevant cancers.

National Institute of Health (NIH)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Korczak, Jeannette F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code