Biomechanics of the Cell Nucleus: The Role of Chromatin and its Connectivity with Nuclear Proteins and the Nuclear Membrane

该奖项的研究目标是研究单个核组分如何有助于细胞核的机械性能，使用一种新的光镊分析法，结合遗传学上容易的裂变酵母S.粟酒在该奖项下进行的研究将测试如何改变细胞核的大小，基因组的压实，核膜的流动性，以及染色质与核膜的关联影响核机械性能。核纤层蛋白是决定哺乳动物细胞核力学性质的关键，但在S.粟酒裂殖酵母，将介绍异源解剖他们的机械性能，从他们在哺乳动物的信号和基因调控的作用。在对S.跨越核膜的粟酒LINC复合体将阐明力是如何传递到核机械网络中的。如果成功的话，这些研究将阐明细胞核的力学是如何从其组成部分中出现的，并描绘出对于产生特定细胞类型的分化程序至关重要的机械环境是如何传递到细胞核的，细胞命运在很大程度上决定于细胞核。他们也将建立S。粟酒裂殖酵母作为一个模型系统，其中核纤层蛋白的机械作用可以从它们的调节功能中分离出来，从而为将来研究引起脂肪营养不良、肌肉营养不良和早衰症等疾病的核纤层蛋白突变体提供了一个平台。由于胚胎干细胞（ES）和酵母表达非常低的水平或没有核纤层蛋白，分别，这些研究也将导致新的见解如何细胞外机械线索驱动ES细胞分化。在教育方面，参与这些研究的学生将成为新一代的教师-科学家，他们擅长定量方法，拥有生物学的复杂性，可以识别和解决尖端的生物学问题。

The research objective of this award is to examine how individual nuclear components contribute to the mechanical properties of the cell nucleus using a novel optical-tweezers assay in conjunction with nuclei from the genetically-facile fission yeast, S. pombe. Studies conducted under this award will test how altering the size of the nucleus, the compaction of the genome, the fluidity of the nuclear membrane, and association of chromatin with the nuclear envelope affect nuclear mechanical properties. Lamins, which are key in determining the mechanical properties of mammalian nuclei, but do not occur natively in S. pombe, will be introduced heterologously to dissect their mechanical properties from their roles in mammalian signaling and gene regulation. Fluorescence imaging of specific chromosome locations during force application to the S. pombe LINC complex, which spans the nuclear membrane, will elucidate how force is communicated into the nuclear mechanical network.If successful, these studies will elucidate how the mechanics of the nucleus emerge from its constituents, and delineate how the mechanical environment, which is essential for the differentiation programs that give rise to specific cell types, is communicated to the nucleus, where cell fate is largely determined. They will also establish S. pombe as a model system in which the mechanical role of lamins can be decoupled from their regulatory functions, thus providing a platform for future studies of lamin mutants that cause such diseases as lipodystrophy, muscular dystrophy, and progeria. Because embryonic stem (ES) cells and yeast express very low levels or no lamins, respectively, these studies will also lead to new insights into how extracellular mechanical cues drive ES cell differentiation. On the educational side, the students involved in these studies will become a new generation of teacher-scientists, who excel at quantitative approaches and possess the biological sophistication to identify and tackle cutting-edge biological problems.