Mechanistic study of Hedgehog signaling in the cilium

项目总结 Hedgehog(HH)信号的缺陷广泛地与各种出生缺陷和癌症有关。这个 HH信号的转导依赖于初级纤毛，一个被认为是 一个信号枢纽。HH信号的核心开关Smo移位到纤毛转动 在HH信号上。在分子水平上，Smo下游的信号机制很差。 明白了。这为针对HH的通路特异性治疗的发展制造了巨大的障碍。 相关的障碍。我们的首要目标是阐明对Smo相关信号的机械论见解。 HH转导过程中的事件。为了实现这一目标，我们建立了一个蛋白质组平台来 系统鉴定Smo相互作用蛋白。我们在这个平台上的初步研究确定了催化剂 PKA亚基作为一种Smo相互作用蛋白。我们将创新进入HH信令的未知领域 通过实现两个目标：1)在以下过程中系统地定义Smo相互作用蛋白质 HH信号转导与功能蛋白质组学；2)破译SMO之间的机制联系 以及纤毛中PKA在HH信号转导和HH相关肿瘤发生中的作用。我们的方法是 创新是因为它使用了尖端的分子工具来回答一个长期存在的问题 HH途径。它的重要性因人们期望它将揭示长期存在的 关于HH通路中Smo信号的问题，这最终将为 HH相关癌症治疗新方法的发展。这笔赠款将给我一个机会 吸引来自代表性不足群体的学生。我的目标是为 这些学生为他们未来在癌症领域的职业追求提供了帮助，有助于使劳动力多样化 癌症研究的基础研究。

PROJECT SUMMARY Defects in Hedgehog (Hh) signaling is widely implicated in various birth defects and cancers. The transduction of Hh signaling relies on the primary cilium, a miniature cell surface organelle viewed as a signaling hub. Smoothened (Smo), the core switch of Hh signaling, translocates to the cilium to turn on the Hh signaling. At the molecular level, the signaling mechanisms downstream of Smo are poorly understood. This creates a large barrier to the development of pathway specific treatments for Hh- related disorders. Our overarching goal is to elucidate mechanistic insights into Smo-related signaling events during Hh transduction. To achieve this goal, we have established a proteomic flatform to systematically identify Smo interacting proteins. Our pilot study in this flatform identified the catalytic subunit of PKA as a Smo interacting proteins. We will innovate into the unknown areas of Hh signaling by achieving two objectives: 1) systematically defining the Smo interacting proteins over the course of Hh signal transduction with functional proteomics; 2) deciphering the mechanistic link between Smo and PKA in the cilium during Hh signal transduction and Hh-related tumorigenesis. Our approach is innovative because it employs cutting-edge molecular tools to answer a long-standing question in the Hh pathway. Its significance is underlined by the expectation that it will shed light on long-standing questions about Smo signaling in the Hh pathway, which will ultimately provide clues for the development of new therapeutical methods for Hh-related cancers. This grant will give me opportunity to engage students from underrepresented groups. My goal is to build solid research foundations for these students for their future pursuit of careers in cancer field, helping to diversify the workforce in basic study of cancers research.