Molecular mechanisms of centriolar triplet microtubule formation

中心粒三联体微管形成的分子机制

• 批准号: 10649539
• 负责人: Jennifer Tong Wang
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649539
• 关键词: Affect; Award; Biological Assay; CRISPR/Cas technology; Cell Cycle; Cells; Cellular Structures; Cellular biology; Centrioles; Centrosome; Cilia; Complex; Cryoelectron Microscopy; Cytoskeleton; Defect; Dependence; Development; Disease; Eukaryota; Foundations; Future; Genetic; Goals; Health; Human; Human Development; In Vitro; Inherited; Label; Lighting; Link; Malignant Neoplasms; Maps; Mediating; Mentors; Microcephaly; Microscopy; Microtubule Triplet; Microtubules; Molecular; Morphology; Mothers; Organelles; Organism; Phase; Postdoctoral Fellow; Proteins; Research; Research Technics; Rest; Role; Signal Transduction; Structure; Syndrome; Techniques; Testing; Training; Transmission Electron Microscopy; Triplet Multiple Birth; Tubulin; Work; alpha Tubulin; beta Tubulin; career; career development; cell motility; ciliopathy; daughter cell; human disease; improved; in vitro Assay; in vivo; insight; member; mutant; organizational structure; protein transport; reconstitution; recruit; self organization; skills; trafficking

Project Summary/Abstract Centrioles are conserved cellular organelles that template cilia for mediating cell signaling and motility, and recruit pericentriolar material to nucleate microtubules as part of the centrosome. Centrioles are extremely stable structures that persist over multiple cell cycles, and centriole number is controlled to ensure that each daughter cell inherits exactly two centrioles from its mother. Defects in centrosome and cilium function have been linked to a wide range of diseases, including cancer, microcephaly, and a set of syndromes known as ciliopathies. Within a centrosome, the older centriole in the pair templates the cilium, and together they form the centriole-cilium complex. Key features of this complex are the compound microtubules, which are a unique arrangement of microtubules linked together: three linked microtubules form the centriolar triplets, and two form the ciliary doublets. These compound microtubules occur only in the centriole-cilium complex, and are required for the structural integrity of the centriole and for protein trafficking in the cilium. Though the morphology of compound microtubules has long been appreciated, little is known about the mechanisms by which these microtubules form specifically at the centriole-cilium complex. In my postdoctoral work, I found that two members of the tubulin superfamily, delta-tubulin and epsilon-tubulin, are required for the centriolar triplet microtubules. The means by which these proteins act are unknown. Here, I propose to determine the mechanisms of compound microtubule formation through an integrated set of aims. Spanning both the mentored and independent phases, these aims will allow me to test the relative contributions of microtubule protofilaments themselves, as well as other proteins including delta- tubulin and epsilon-tubulin, to compound microtubule formation and stability. With the help of an outstanding collaborator and mentor team, I will train in research techniques, as well as skills for my career development. Together, this will create a strong foundation for an independent research career in understanding the roles of microtubule structures in human development and health.

项目总结/摘要 中心粒是保守的细胞器，其模板纤毛用于介导细胞信号传导和运动， 并募集中心粒周围的物质使微管成核成为中心体的一部分。中心粒非常 在多个细胞周期中持续存在的稳定结构，控制中心粒数量以确保每个细胞周期都有稳定的结构。 子细胞从其母细胞继承了两个中心粒。中心体和纤毛功能缺陷， 与广泛的疾病有关，包括癌症，小头畸形，以及一系列被称为 纤毛病变 在一个中心体内，成对中心粒中较老的中心粒模板纤毛，它们一起形成 中心粒纤毛复合体这种复合体的关键特征是复合微管，这是一种独特的 连接在一起的微管排列：三个连接的微管形成中心粒三联体，两个连接的微管形成中心粒三联体。 形成纤毛双联体。这些复合微管只出现在中心粒-纤毛复合体中， 中心粒的结构完整性和纤毛中的蛋白质运输所需。虽然 复合微管的形态学一直受到重视，但对复合微管的作用机制知之甚少。 这些微管专门在中心粒纤毛复合体上形成。在我的博士后工作中，我发现 微管蛋白超家族的两个成员，δ-微管蛋白和ε-微管蛋白，是中心粒三联体所必需的 微管这些蛋白质的作用方式尚不清楚。 在这里，我建议确定复合微管形成的机制，通过一个 一套完整的目标。跨越了指导阶段和独立阶段，这些目标将允许我测试 微管原丝本身的相对贡献，以及其他蛋白质，包括δ- 微管蛋白和ε-微管蛋白，以复合微管的形成和稳定。在一位杰出的 作为一个合作者和导师团队，我将接受研究技术和职业发展技能的培训。 总之，这将为独立的研究生涯奠定坚实的基础，以了解 微管结构在人类发育和健康中的作用。