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在人类疾病中很重要，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的正常生理学：它是如何被加工成其脂质修饰的形式，并被运输和分泌出细胞，以同时发挥短距离和长距离信号分子的功能。我们将从两个方向来解决这个问题，首先集中在一种与远程信号有关的Shh的贩运和分泌上。我们的第二种方法将是揭示Shh生物发生的各个步骤，这些步骤被在人类发育障碍中发现的Shh突变所破坏，这种疾病被称为全前脑(HPE)。结合起来，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以用来设计预防或治疗各种人类疾病的策略，这些疾病是由解除调控的Shh途径引起的。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病理中被破坏。在实现这些目标之前，我们首先必须了解Shh的正常生理学：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。通过这项工作获得的知识可以用于设计预防或治疗策略，以应对因SHH途径失控而导致的不同人类病理。

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.