Mechanistic study of Hedgehog signaling in the cilium

纤毛中 Hedgehog 信号传导的机制研究

• 批准号: 10527729
• 负责人: Xuecai Ge
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527729
• 关键词: Area; Binding; Binding Proteins; Biomedical Research; California; Catalytic Domain; Cell Line; Cell surface; Cells; Cilia; Collaborations; Communities; Comprehension; Congenital Abnormality; Cyclic AMP-Dependent Protein Kinases; Defect; Development; Disease; Economically Deprived Population; Erinaceidae; Event; Foundations; Future; Goals; Grant; In Vitro; Integral Membrane Protein; Label; Ligands; Light; Link; Malignant Neoplasms; Mediating; Membrane; Methods; Molecular; Monitor; Nature; Nodal; Organelles; Outcome; Pathway interactions; Phase; Pilot Projects; Play; Process; Proteins; Proteomics; Recruitment Activity; Regulation; Research; Research Project Grants; Rest; Role; Signal Transduction; Solid; Student recruitment; Students; System; Therapeutic Intervention; Time; Training; Transducers; Underrepresented Populations; Underrepresented Students; anticancer research; base; career; expectation; hedgehog signal transduction; in vivo; innovation; insight; mouse model; novel therapeutic intervention; novel therapeutics; protein transport; smoothened signaling pathway; stable cell line; therapeutic development; tool; transcription factor; tumorigenesis

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.

项目摘要 刺猬（HH）信号的缺陷广泛涉及各种出生缺陷和癌症。这 HH信号传导的转导取决于原发性纤毛，一个微型细胞表面细胞器被视为 信号轮毂。平滑（SMO），HH信号的核心开关，转移到纤毛转向 在HH信号传导上。在分子水平上，SMO下游的信号传导机制很差 理解。这为HH-的途径特定治疗的发展造成了巨大的障碍 相关疾病。我们的总体目标是阐明机械洞察到与SMO相关的信号传导 HH转导期间的事件。为了实现这一目标，我们已经建立了一个蛋白质组学扁平化 系统地识别SMO相互作用蛋白。我们在此扁平化中的试点研究确定了催化性 PKA作为SMO相互作用蛋白的亚基。我们将创新进入HH信号的未知区域 通过实现两个目标：1）在整个过程中系统地定义SMO相互作用的蛋白 HH信号转导具有功能蛋白质组学； 2）解密SMO之间的机械链接 在HH信号转导和HH相关肿瘤发生过程中，纤毛中的PKA和PKA。我们的方法是 创新性是因为它采用尖端的分子工具来回答一个长期存在的问题 HH路径。它的意义强调了它将阐明长期存在的期望 有关HH途径中SMO信令的问题，该问题最终将为该路径提供线索 开发用于HH相关癌症的新治疗方法。这笔赠款会给我机会 吸引来自代表性不足的团体的学生。我的目标是为 这些学生未来追求癌症领域的职业，有助于使劳动力多样化 癌症研究的基础研究。