The role of microtubule dynamics in midzone driven chromosome segregation in anaphase

微管动力学在中区驱动的后期染色体分离中的作用

基本信息

批准号：
10797668
负责人：
Stefanie Redemann
金额：
$ 20.7万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-03 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10797668
关键词：
3-Dimensional Anaphase Automobile Driving Bundling Cell division Cells Chromosome Segregation Chromosomes Complement Coupled Data Development Failure Generations Genetic Genomics Goals Growth Guanine Nucleotide Exchange Factors Health Human Individual Kinesin Kinetochores Length Life Light Longevity Malignant Neoplasms Mathematical Model Simulation Measurement Metaphase Plate Microscopic Microtubule Bundle Microtubule Polymerization Microtubules Mitosis Mitotic spindle Modeling Molecular Monitor Motor Nature Optics Organism Pathway interactions Play Plus End of the Microtubule Polymers Positioning Attribute Process Property Proteins Publications RNA Interference Regulation Research Resolution Role Running Sister Chromatid Slide Solid Source Structure System Testing Time Visualization chromosome movement daughter cell electron tomography genetic approach insight light microscopy mathematical model mutant new therapeutic target novel novel therapeutic intervention polymerization prevent recruit segregation targeted cancer therapy tomography

项目摘要

Summary The faithful segregation of chromosomes during mitosis is a fundamental and important process, happening approximately a quadrillion time throughout a human life span. Errors in mitosis have severe implications and are often detrimental to development, health and survival of the organism. Microtubules are the main building blocks of mitotic spindles and are a very important target for cancer therapy. We know that microtubules, in particular kinetochore microtubules, exert forces on chromosomes to initially position them on the metaphase plate and consequently divide them to the two daughter cells. However, recent research has shown that the central spindle also plays an important role in chromosome segregation. The precise mechanisms of how the central spindle regulates chromosome segregation are not fully understood today. A line of evidence has suggested that the central spindle can generate outward pushing forces to move chromosomes, but it has also been convincingly shown to slow chromosome segregation down by acting like a break. The goal of this proposal is to dissect the function of the central spindle during anaphase and to identify how the central spindle generates forces contributing to the segregation of chromosomes. We further aim to establish the contribution of microtubule dynamics for central spindle function. To achieve this goal, we use the microstructural data from tomography in wild type and mutant conditions to monitor the microtubule arrangement and properties in the central spindle during anaphase and to identify potential interactions and force generating mechanisms. We will complement the precise structural data with dynamic data on microtubules in the midzone obtained by cutting edge light-microscopic analysis. We will use mathematical modeling to develop and test hypothesis of how the spindle midzone contributes to chromosome segregation in anaphase. The ultimate goal of our study is to understand how the central spindle generates forces that regulate the segregation of chromosomes and to identify the molecular key players of this process

概括有丝分裂期间染色体的忠实分离是一个基本而重要的过程，正在发生在整个人类的生活范围内，大约四千万的时间。有丝分裂的错误具有严重的影响，并且通常不利于生物体的发育，健康和生存。微管是主要建筑物有丝分裂纺锤体的块，是癌症治疗的非常重要的靶标。我们知道微管，特定的动力学微管，在染色体上施加力最初将其定位在中期上板并因此将它们分为两个子细胞。但是，最近的研究表明中央主轴在染色体分离中也起着重要作用。如何确切机制当今的中央主轴调节染色体分离尚未完全了解。证据有建议中央主轴可以产生向外推力以移动染色体，但也有令人信服地证明，通过表现得像休息一样降低了染色体隔离。目标的目标建议是在后期期间剖析中央主轴的功能，并确定中央主轴产生有助于染色体分离的力。我们进一步旨在建立贡献用于中央主轴函数的微管动力学。为了实现这一目标，我们使用微观结构数据从野生型和突变条件下的断层扫描到监测微管布置和特性后期期间的中央主轴，并确定潜在的相互作用和力产生机制。我们将与精确的结构数据与微管中的微管的动态数据进行补充。尖端微型微观分析。我们将使用数学建模来开发和检验纺锤体中区如何促进后期染色体分离。我们学习的最终目标是要了解中央主轴如何产生调节染色体隔离的力和确定此过程的分子关键参与者