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

中心体由一对9倍对称的桶状结构组成，中心粒被许多蛋白质包围，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重要的细胞结构，当染色体生长和分裂时，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织的，没有正常功能的中心体，有丝分裂纺锤体将不能正确形成。因此，在没有功能性中心体的情况下，染色体不能准确地分离到每个子细胞，从而导致一种称为非整倍体的情况，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，我们最近使用超分辨率显微镜发现PCM比通常认为的要有序得多。特别是，我们发现不同的PCM蛋白根据其在中心体生物学调节中的功能占据不同的空间结构域。该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时空地图。此外，我们将研究已知的中心体蛋白在中心体结构域组织中的作用，并确定这一过程的新调控因子。总的来说，这项工作将导致对中心体组织和组装以及它们在细胞周期中如何被调节的机制有更好的理解。

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.