Deciphering pericentriolar material architecture and assembly principles using sub-diffraction imaging.

中心体是由一对9重对称的桶形结构组成的中心粒，其周围包裹着许多蛋白质，统称为中心粒周围物质（PCM）。PCM负责中心体生物发生和功能的几个方面，包括微管的成核和锚定。有丝分裂纺锤体是一种基本的细胞结构，在后代细胞生长和分裂时，它在物理上执行准确地将染色体传递给后代细胞的任务。有丝分裂纺锤体的两极是由中心体组成的，如果没有功能正常的中心体，有丝分裂纺锤体就不能正确形成。因此，在没有功能性中心体的情况下，染色体不会准确地分离到每个子细胞，导致称为非整倍性的情况，这种情况可能导致癌症等毁灭性疾病。传统上被描述为无定形的，我们最近发现，使用超分辨率显微镜，PCM比通常认为的要有序得多。特别是，我们发现，不同的PCM蛋白占据不同的空间结构域，符合其功能的中心体生物学的调节。这项提案的主要目标是建立在这一令人兴奋的新发现的基础上，并生成人类中心体的高分辨率空间和时间图。此外，我们还将研究已知的中心体蛋白在中心体结构域的组织中的贡献，并确定这一过程的新调节剂。总的来说，这项工作将导致更好地了解中心体组织和组装以及它们在细胞周期中如何调节。

Centrosomes are composed of a pair of 9-fold symmetric barrel-shaped structures coined centrioles, which are surrounded by many proteins collectively referred to as pericentriolar material (PCM). PCM is responsible for several aspects of centrosome biogenesis and function including the nucleation and anchoring of microtubules. The mitotic spindle is an essential cellular structure that physically carries out the task of accurately transmitting chromosomes to progeny cells as they grow and divide. The two poles of the mitotic spindle are organized by centrosomes and without properly functioning centrosomes, the mitotic spindle will not form correctly. Therefore, in the absence of functional centrosomes, chromosomes would not segregate accurately to each daughter cell leading to a condition called aneuploidy that can cause devastating diseases like cancer. Traditionally described as amorphous, we have recently discovered using super-resolution microscopy that the PCM is much more ordered than generally thought. In particular, we found that different PCM proteins occupy distinct spatial domains in line with their functions in the regulation of centrosome biology. The major objective of this proposal is to build on this exciting new discovery and generate high-resolution spatial and temporal maps of the human centrosome. In addition, we will study the contribution of known centrosome proteins in the organization of centrosome domains and identify novel regulators of this process. Overall, this work will lead to a better mechanistic understanding of centrosome organization and assembly and how they are regulated during the cell cycle.