Characterization of Sonic Hedgehog Biogenesis

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DESCRIPTION (provided by applicant): Deregulation of the Sonic Hedgehog (Shh) signal transduction pathway results in a number of human developmental disorders and contributes to a diverse array of tumors. Despite the importance of Shh in human disease, basic questions regarding the biogenesis of Shh remain poorly understood. Here, we propose to elucidate the normal physiology of Shh: how it is processed into its lipid modified form, trafficked and secreted out of the cell to function as both a short-range and long-range signaling molecule. We will approach this question from two directions, initially focusing on the trafficking and secretion of a form of Shh implicated in long-range signaling. Our second approach will be to uncover the various steps in Shh biogenesis that are disrupted by the Shh mutations identified in the human developmental disorder known as holoprosencephaly (HPE). Combined, our approach will identify important steps in the production, trafficking, activity and secretion of Shh. The knowledge gained upon completion of this work could be used to design preventative or curative strategies for the various human pathologies that result from a deregulated Shh pathway. PUBLIC HEALTH RELEVANCE: The long-term goal of our research is to elucidate how the secreted protein Sonic Hedgehog (Shh) contributes to human development, and how this regulation is disrupted in various human pathologies. Prior to achieving these goals, we will first have to understand the normal physiology of Shh: how it is presented to receiving cells and how these cells interpret this signal. The knowledge gained as a result of this work could be used to design preventative or curative strategies for the different human pathologies that result from a deregulated Shh pathway.