Micromechanical Analysis of Chromosome Structure

染色体利用储存在DNA结构中的遗传信息，直接控制着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，但它们必须被精确地复制，然后将复制的DNA分子彼此分离，以便每次细胞分裂产生的子细胞拥有一套完整的基因。染色体分离的过程至关重要地依赖于它们的整体结构，而在细胞分裂过程中，它们的整体结构发生了巨大的变化：当细胞准备分裂时，它们的染色体从未展开的状态变为紧凑的、紧密折叠的圆柱形结构。该项目旨在了解在细胞分裂过程中染色体是如何折叠成这种“有丝分裂”形式的，并将首次直接研究负责染色体折叠的特定分子之间的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分子之间相互作用的强度：单个染色体将从分裂的细胞中移除，然后使用微小的（微米级）力测量探针直接测量它们的机械性能。本项目旨在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，这些特定蛋白质在保持染色体在一起方面的作用将被确定。此外，本项目将使用相同的方法来确定染色体不同部分的折叠相对强度，并建立研究细胞分裂之间染色体机制的方法。更广泛的影响：本项目将通过新颖的实验对大规模染色体结构的开放性问题产生广泛的影响。大聚合物的结构和拓扑结构的调节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的观众感兴趣。这项生物学和物理学交叉的跨学科研究将培养定量生物学的研究生，这是一个大学对初级教师需求量很大的领域。为高中生和本科生提供研究经验也将产生更广泛的影响，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代表性不足的少数群体成员填补各级研究职位。

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.