Post-transcriptional mechanisms of centrosome regulation

项目摘要 中心体失调是遗传性小头畸形的主要原因，这是一种典型的先天性出生缺陷 与智力残疾和发育迟缓有关。中心体功能障碍也被认为是一种 癌症的关键驱动因素和预后标志。然而，中心体调控的潜在机制仍然存在。 不完全理解。中心体在组成和组织上经历细胞周期依赖性的变化 来调节它们作为微管组织中心的活动，这些振荡有助于 中心体功能。中心体的一个动态成分是信使核糖核酸，但信使核糖核酸的功能作用 对中心体的定位仍然知之甚少。在这项建议中，我们研究了信使核糖核酸是否有助于 中心体的调节和功能。在目标1中，我们定义了信使核糖核酸定位的机制 中心体。在目标2中，我们揭示了两个保守的RNA结合蛋白的调节作用。目标3 检测定位于中心体的信使核糖核酸的功能。这项工作的完成将解决长期- 关于定位于中心体的信使核糖核酸在遗传易控模型中的作用的悬而未决的问题。这 这项工作将有助于我们理解中心体调控，在某些情况下，中心体调控的各个方面是不受管制的 小头畸形症和癌症。

Project Summary Centrosome deregulation is the leading cause of heritable microcephaly, a congenital birth defect typically associated with intellectual disabilities and developmental delay. Centrosome dysfunction is also considered a key driver and prognostic marker of cancer. Yet, mechanisms underlying centrosome regulation remain incompletely understood. Centrosomes undergo cell cycle-dependent changes in composition and organization to modulate their activity as microtubule-organizing centers, and these oscillations contribute to the diversity of centrosome functions. One dynamic constituent of centrosomes is mRNA, yet the functional role of mRNA localized to centrosomes remains poorly understood. In this proposal, we examine whether mRNA contributes to centrosome regulation and functions. In Aim 1, we define mechanisms of mRNA localization to centrosomes. In Aim 2, we uncover the regulatory contributions of two conserved RNA-binding proteins. Aim 3 examines the function of mRNA localized to centrosomes. The completion of this work will address long- standing questions about the role of mRNA localized to centrosomes within a genetically tractable model. This work will contribute to our understanding of centrosome regulation, aspects of which are deregulated in cases of microcephaly and cancer.