Micromechanical Analysis of Chromosome Structure

染色体结构的微观力学分析

• 批准号: 1022117
• 负责人: John Marko
• 金额: $ 78.04万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1022117&HistoricalAwards=false
• 关键词: Micromechanical; Analysis; Chromosome; Structure

Chromosomes directly control the growth and development of all living organisms, using genetic information stored in the structure of their DNA. The DNA molecules in human chromosomes are more than a centimeter long, or roughly 1000 times longer than the cells in which they are found, yet they must be precisely replicated and then the duplicates separated from one another, in order for daughter cells resulting from each cell division to have a complete set of genes. The process of chromosome segregation is crucially dependent on their overall structure, which is dramatically changed during cell division: as cells prepare to divide, their chromosomes change from an unfolded state to compact, tightly folded cylindrical structures. This project is aimed at understanding how chromosomes are folded into this "mitotic" form occurring during cell division, and will provide, for the first time, direct study of forces provided by interactions between the specific molecules responsible for folding of the chromosome. A unique technology will be used to probe the strength of interactions between molecules inside chromosomes: individual chromosomes will be removed from dividing cells, and then their mechanical properties will be directly measured, using tiny (micron-scale) force-measuring probes. This project will seek to study the functions of specific molecules in the folding of chromosomes during cell division. By suppressing production of specific proteins and then observing changes in the mechanical properties and overall folding of mitotic chromosomes, the roles of those specific proteins in holding the chromosome together will be determined. Also, this project will use the same approach to determine the relative strength of folding of different parts of chromosomes, and also establish methods to study the mechanics of chromosomes between cell divisions.Broader Impacts: This project will achieve broad impact through novel experiments on the open questions concerning large-scale chromosome structure. The general problem of regulation of structure and topology of large polymers is of interest to a highly interdisciplinary audience of biologists, physicists, materials scientists, chemists and engineers. This interdisciplinary research at the interface between biology and physics will train graduate students in quantitative biology, an area in which junior faculty is in heavy demand by universities. Broader impacts will also be achieved by providing research experience to high school and undergraduate students who otherwise might not have access to university-level scientific research. Priority will be given to filling research positions at all levels with women and members of underrepresented minority groups.

染色体利用储存在DNA结构中的遗传信息直接控制所有生物体的生长和发育。人类染色体中的DNA分子长度超过一厘米，大约是它们所在细胞的1000倍，但它们必须精确复制，然后将复制品彼此分离，以便每次细胞分裂产生的子细胞具有完整的基因组。染色体分离的过程关键取决于它们的整体结构，这在细胞分裂过程中发生了巨大的变化：当细胞准备分裂时，它们的染色体从展开状态变为紧凑，紧密折叠的圆柱形结构。 该项目旨在了解染色体如何折叠成细胞分裂期间发生的这种“有丝分裂”形式，并将首次直接研究负责染色体折叠的特定分子之间相互作用所提供的力。 一项独特的技术将用于探测染色体内部分子之间相互作用的强度：将单个染色体从分裂的细胞中取出，然后使用微小的（微米级）测力探针直接测量它们的机械性能。该项目将寻求研究细胞分裂过程中染色体折叠中特定分子的功能。通过抑制特定蛋白质的产生，然后观察有丝分裂染色体的机械特性和整体折叠的变化，将确定这些特定蛋白质在保持染色体在一起中的作用。 此外，还将利用同样的方法测定染色体不同部分的相对折叠强度，并建立细胞分裂间染色体力学的研究方法。影响范围：通过对大规模染色体结构的开放性问题进行新的实验，将产生广泛的影响。大型聚合物的结构和拓扑调控的一般问题是生物学家，物理学家，材料科学家，化学家和工程师的高度跨学科观众感兴趣的。 在生物学和物理学之间的接口跨学科研究将培养研究生在定量生物学，在初级教师是在大学的大量需求领域。还将通过向高中生和本科生提供研究经验来实现更广泛的影响，否则他们可能无法获得大学水平的科学研究。将优先考虑由妇女和任职人数不足的少数群体成员填补各级研究职位。