Characterization of Sonic Hedgehog Biogenesis

描述（由申请人提供）：Sonic Hedgehog （Shh）信号转导通路的解除管制导致许多人类发育障碍，并导致多种肿瘤。尽管Shh在人类疾病中的重要性，但关于Shh的生物发生的基本问题仍然知之甚少。在这里，我们建议阐明Shh的正常生理：它如何被加工成脂质修饰形式，运输并分泌出细胞，作为短程和远程信号分子发挥作用。我们将从两个方向来解决这个问题，首先关注与远程信号有关的Shh的一种形式的贩运和分泌。我们的第二种方法将是揭示Shh生物发生的各个步骤，这些步骤被人类发育障碍称为前脑畸形（HPE）的Shh突变所破坏。综合起来，我们的方法将确定Shh的生产、贩运、活动和分泌的重要步骤。完成这项工作后获得的知识可用于设计由Shh通路失调引起的各种人类病理的预防或治疗策略。公共卫生相关性：我们研究的长期目标是阐明分泌蛋白Sonic Hedgehog （Shh）如何促进人类发育，以及这种调节如何在各种人类疾病中被破坏。在实现这些目标之前，我们首先必须了解Shh的正常生理：它是如何呈现给接收细胞的，以及这些细胞如何解释这个信号。这项工作所获得的知识可用于设计预防或治疗由Shh通路失调引起的不同人类病理的策略。

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.