Chemical disruption of the Hh and Wnt pathways in vertebrate development

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DESCRIPTION (provided by applicant): An abundance of evidence supports a role for aberrant cellular responses to developmentally important signaling molecules in the biogenesis of cancer. The therapeutic value of agents being developed to target these pathways, such as those controlled by the Hedgehog and Wnt signaling molecules are likely to be diminished in children or child-bearing women due to the dependency of normal developmental processes on these pathways. The long-term goal of our research is to understand the mechanisms that would enable us to target such pathways in disease with minimal consequences to normal developmental processes. In this proposal, we will uncover the interactions of two novel inhibitors of the Hh and Wnt/2-catenin signal transduction pathways with developing tissues in vertebrates using zebrafish as a model organism. In identifying the developmental processes that are influenced by transient exposure to these small molecules, we will establish the necessary knowledgebase to successfully predict and minimize unwanted effects from therapeutic targeting of these developmental and oftentimes cancerous pathways. PUBLIC HEALTH RELEVANCE: In the last decade, significant advances have been made toward achieving chemical control of key developmental signal transduction pathways that are frequently corrupted in cancer. Given the promise of these therapeutic strategies and the perils that they pose for developing individuals, we propose to systematically chronicle the consequences from the chemical inhibition of two such pathways controlled by the Hedgehog and Wnt signaling molecules in vertebrate embryogenesis and adolescent growth. The findings from this proposal should provide a strategic framework for predicting and countering unwanted effects that are associated with the use of such therapeutic reagents.