Mechanistic study of Hedgehog signaling in the cilium

项目摘要 Hedgehog（Hh）信号传导缺陷广泛涉及各种出生缺陷和癌症。的 Hh信号转导依赖于初级纤毛，初级纤毛是一种微型细胞表面细胞器， 一个信号中心Smoothened（Smo）是Hh信号转导的核心开关， 在Hh信号上。在分子水平上，Smo下游的信号传导机制很差， 明白这对Hh途径特异性治疗的发展造成了很大的障碍- 相关疾病。我们的首要目标是阐明与Smo相关的信号转导机制 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学平台， 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Smo相互作用蛋白。我们将创新进入Hh信号传导的未知领域 通过实现两个目标：1）系统地定义Smo相互作用蛋白的过程中， Hh信号转导与功能蛋白质组学; 2）破译Smo 和PKA在纤毛中的Hh信号转导和Hh相关的肿瘤发生。我们的做法是 创新，因为它采用了尖端的分子工具来回答一个长期存在的问题， Hh途径。它的重要性突出表现在人们期望它将揭示长期存在的 关于Hh通路中Smo信号传导的问题，这将最终为Hh通路的研究提供线索。 开发Hh相关癌症的新治疗方法。这笔补助金将给我一个机会 来吸引来自弱势群体的学生。我的目标是建立坚实的研究基础， 这些学生为他们未来追求的职业生涯在癌症领域，帮助多样化的劳动力， 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.