Characterization of Sonic Hedgehog Biogenesis

Sonic Hedgehog（Shh）信号转导通路的失调导致许多人类免疫缺陷综合征。 发育障碍并导致多种肿瘤。尽管嘘的重要性， 人类疾病，关于Shh的生物起源的基本问题仍然知之甚少。这里我们 我建议阐明Shh的正常生理学：它是如何被加工成脂质修饰形式的， 并分泌到细胞外，作为短程和远程信号分子发挥作用。我们将 我从两个方向来探讨这个问题，最初集中在一种嘘的运输和分泌上， 与远程信号有关我们的第二种方法是揭示Shh中的各个步骤 生物发生被Shh突变破坏，Shh突变在人类发育障碍中被称为 前脑无裂畸形。结合起来，我们的方法将确定生产中的重要步骤， Shh的运输、活动和分泌。完成这项工作后获得的知识可以用于 设计预防或治疗策略的各种人类病理，导致从放松管制， 嘘通道。

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.