Mechanisms of Hedgehog Signal Transduction

项目总结

PROJECT SUMMARY The evolutionarily conserved Hedgehog (Hh) signaling pathway governs tissue morphogenesis during development and contributes to tissue homeostasis in adults. Alteration of pathway activity drives developmental disorders including Holoprosencephaly (HPE), Pallister-Hall Syndrome and Basal Cell Nevus syndrome. Inappropriate activation of signaling post-developmentally is frequently associated with cancer, being causative in basal cell carcinoma and medulloblastoma, and implicated as a survival factor in a range of additional tumor types. As such, there is significant interest and therapeutic potential in defining the mechanisms governing Hh pathway activity. My laboratory's long-term goal is to define the regulatory processes governing Hh pathway activity during development, and use this knowledge to identify opportunities for targeting inappropriate Hh signaling in disease. Over the next 5 years, we will continue to work toward this goal by interrogating and defining the molecular mechanisms controlling pivotal regulatory steps of the Hh signal transduction cascade. We are focused on elucidating 1) how Hh ligand release and transport are controlled to establish a morphogen gradient, 2) how Smo activation, signal bias and effector engagement are controlled during development and corrupted in disease, and 3) how Gli transcriptional activator induction and destabilization are coordinated to assure an appropriate transcriptional response.