Microtubule Organization and Nuclear Positioning

描述(申请人提供)：微管是负责细胞空间组织的细胞骨架元素。它们执行关键的细胞过程，如染色体分离、细胞极化和细胞迁移。MT Plus末端的动态行为--它们的生长、收缩、靶向和附着--受到一系列MT相关因子的调节。在这里，我们以裂殖酵母庞贝裂殖酵母为模式生物，研究MT细胞骨架调控的分子机制。我们的研究集中在阐明MT生长和萎缩之间的调节机制，即MT救援和灾难。我们的目标是：1)鉴定候选MT救援因子CLAP，它可以稳定有丝分裂纺锤体和间期MT束中的MT；2)确定MT灾难事件发生在细胞顶端特定皮质部位的原因；3)研究肌动蛋白在细胞核中的可能作用，重点是它在有丝分裂过程中对染色体分离的影响。 公共卫生相关性：微管是负责细胞分裂和决定细胞形状和功能的动态细丝。在这项提案中，我们将确定微管的生长和收缩是如何调节的。这些研究将提供对有丝分裂纺锤体如何工作的更多了解，并将与癌症等人类疾病相关。

DESCRIPTION (provided by applicant): Microtubules are cytoskeletal elements responsible for the spatial organization of cells. They carry out critical cellular processes such as chromosome segregation, cell polarization and cell migration. The dynamic behaviors of MT plus ends - their growth, shrinkage, targeting and attachment -- are modulated by a bevy of MT-associated factors. Here, we study the molecular mechanisms that regulate the MT cytoskeleton, using the fission yeast Schizosaccharomyces pombe as a model organism. Our studies focus on elucidating the mechanisms that regulate the transitions between MT growth and shrinkage, namely MT rescue and catastrophe. Our aims are: 1) to characterize CLASP, a candidate MT rescue factor that stabilizes MTs within the mitotic spindle and interphase MT bundles; 2) to determine why MT catastrophe events occur at specific cortical sites at cell tips; 3) to investigate possible roles of actin in the nucleus, focusing on its effect on chromosome segregation during mitosis. PUBLIC HEALTH RELEVANCE: Microtubules are dynamic filaments responsible for cell division and determination of cell shape and function. In this proposal we will determine how the growth and shrinkage of microtubules are regulated. These studies will provide greater understanding of how mitotic spindles work and will be relevant for human diseases such as cancer.