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.
TO HUMAN DISEASE The Hedgehog (Hh) signal transduction pathway plays an essential role in patterning fields of cells during development, and is frequently activated in cancer. Attenuation of Hh signaling during development leads to developmental syndromes such as Holoprosencephaly and Pallister-Hall Syndrome. Conversely, inappropriate activation of Hh signaling is causative in basal cell carcinoma, the most common cancer in humans, medulloblastoma, the most common malignant brain tumor in children, and rhabdomyosarcoma, where pathway activation correlates with poor prognosis. In addition, Hh ligand that is produced by tumor cells has been reported to function in both autocrine and paracrine manners to promote tumor survival. As such, the Hh pathway has emerged as an attractive therapeutic target. The goals of this proposal are to dissect regulatory mechanisms controlling Hh pathway activity, focusing on understanding 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. We will achieve these goals through comprehensively analyzing pathway activity using biochemical, cell biological and genetic model systems. Knowledge obtained during the course of the proposed studies will enhance our understanding of the mechanisms controlling an essential developmental signaling cascade, and may reveal novel methods of targeting aberrant Hh signaling in disease.
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