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

• 批准号: 10345098
• 负责人: Stefanie Redemann
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10345098
• 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; Sister Chromatid; Slide; Solid; Source; Structure; System; Testing; Time; 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

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

总结 在有丝分裂过程中染色体的忠实分离是一个基本而重要的过程， 大约是人类一生中的四分之一秒。有丝分裂中的错误有严重的影响， 通常对生物体的发育、健康和存活有害。微管是 有丝分裂纺锤体块，是癌症治疗的一个非常重要的靶点。我们知道微管， 特别是动粒微管，对染色体施加力，使它们最初定位在中期 然后将它们分成两个子细胞。然而，最近的研究表明， 纺锤体在染色体分离中也起重要作用。如何精确的机制， 纺锤体调控染色体分离的机制至今尚未完全阐明。一系列证据表明 表明，中央纺锤体可以产生向外的推力来移动染色体，但它也 令人信服地证明了它可以通过断裂来减缓染色体分离。这个目标 建议剖析纺锤体在分裂后期的功能，并确定纺锤体如何在分裂后期发挥作用 产生有助于染色体分离的力。我们进一步的目标是建立贡献 微管动力学对中央纺锤体功能的影响。为了实现这一目标，我们使用显微结构数据 通过野生型和突变条件下的断层扫描来监测微管排列和性质 在后期的中央主轴，并确定潜在的相互作用和力产生机制。 我们将补充精确的结构数据与动态数据微管在中间区获得的， 尖端的光学显微镜分析我们将使用数学建模来开发和测试假设， 纺锤体中间区对后期染色体分离的影响。我们研究的最终目的 是为了了解中央纺锤体如何产生调节染色体分离的力量， 确定这一过程的分子关键参与者