Molecular mechanisms of centriolar triplet microtubule formation

项目摘要/摘要 中心粒是一种保守的细胞器，它以纤毛为模板，调节细胞信号和运动， 并招募中心体周围物质形成微管作为中心体的一部分。中心粒是极其重要的 稳定的结构在多个细胞周期中持续存在，中心粒数量受到控制，以确保每个 子代细胞正好从母体那里继承了两个中心粒。中心体和纤毛功能缺陷有 与一系列疾病有关，包括癌症、小头畸形症和一系列被称为 纤毛病。 在中心体内，两个中心体中较老的中心粒形成纤毛模板，它们共同形成 中心粒-纤毛复合体。这种复合体的主要特征是复合微管，这是一种独特的 连接在一起的微管的排列：三个连接的微管形成中心粒三联体，两个 形成纤毛双胞胎。这些复合微管只出现在中心粒-纤毛复合体中，并且 中心粒的结构完整性和纤毛中的蛋白质运输所必需的。虽然 复合微管的形态长期以来一直受到重视，但对其机制知之甚少。 这些微管专门在中心粒-纤毛复合体形成。在我的博士后工作中，我发现 中心粒三联体需要微管蛋白超家族的两个成员，即微管蛋白和微管蛋白。 微管。这些蛋白质的作用方式尚不清楚。 在这里，我建议通过一种新的方法来确定复合微管的形成机制。 一套完整的目标。在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，以及包括Delta-2在内的其他蛋白质。 微管蛋白和epsilon-微管蛋白，以促进复合微管的形成和稳定。在一位杰出人士的帮助下 作为合作者和导师团队，我将在研究技能以及我的职业发展技能方面进行培训。 总而言之，这将为独立的研究生涯奠定坚实的基础，了解 微管结构在人类发育和健康中的作用

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.