The Wnt pathway is an evolutionarily conserved signaling pathway present in all metazoans. During development, Wnt signaling coordinate the formation of tissues, organs, and limbs, and its misregulation leads to a variety of human disease states such as Alzheimer's and cancer. The Ethan Lee lab is interested in understanding the basic mechanism by which a Wnt signal is propagated and how this information is used to pattern the organism. They are also interested in how this information could be used in regenerative medicine and in the treatment of cancer.
A major experimental approach in the Lee lab involves the use of Xenopus extracts and purified proteins to biochemically reconstitute Wnt signaling in vitro. Mathematical modeling, Genome-scale screens, cultured mammalian cells, Xenopus embryos, and mouse studies are employed to compliment and extend our biochemical findings.
One of the major mysteries of this pathway is how a Wnt signal is propagated from the cell surface. The Lee lab has recently developed an in vitro system to study the mechanism of Wnt signal transduction from the plasma membrane. Towards this end, they have focused on understanding the mechanism of signaling from the co-receptor, LRP6, in Wnt signal transduction. Another major question the Lee lab is interested in is the mechanism by which the transcriptional coactivator, b-catenin, is degraded by the ubiquitin/proteasome system. Recently, lab members have undertaken a genome-scale screen to identify deubiquitinating enzyme (DUBs) and ubiquitin ligases (E3s) that regulate the Wnt pathway. They found that one of the E3 that they identified in this screen is required for Wnt signaling, and are currently characterizing its exact role in Wnt signaling and during Xenopus development.
Modern regenerative medicine is a field in which stem cells are manipulated to treat a variety of human diseases. Wnt signaling is one of a handful of molecular pathways critical to stem cells. Thus, agents that target Wnt signaling would be potentially useful for the treatment of cardiovascular disease, diabetes, neurodegeneration, and other disorders. Cancer stem cells (CSC) are fundamental to the initiation and maintenance of tumors. Failure to eradicate CSC (as is typical with conventional therapy) leaves behind a small reservoir of cells that drives relapse. Wnt inhibitors would be expected to specifically target this resistant CSC population. Using their Xenopus biochemical system, the Lee lab has identified a small molecule that potently inhibits the Wnt pathway. Current efforts are directed towards characterizing the molecular target of this small molecule. In addition to small molecules, the Lee lab is also exploring neutralizing antibodies against the Wnt pathway.
Postdoctoral Positions Available
A postdoctoral position is available to study the Wnt pathway using primarily biochemical approaches. Possible projects include 1) reconstitution of key aspects of the Wnt pathway, 2) small molecule screen for Wnt pathway inhibitors, and 3) characterization of newly identified regulators of the Wnt pathway. Highly motivated applicants who have significant experience in protein expression and purification as well as some experience working with cultured cells would be preferred. The successful applicant would be encouraged to take a part of the project with him/her in order to begin an independent research program upon completion of the fellowship. Applicants should send a cover letter, CV, and names of three references to email@example.com.