Mechanisms of cell shape change in cytokinesis

胞质分裂中细胞形状变化的机制

基本信息

批准号：
10582156
负责人：
Amy Shaub Maddox
金额：
$ 24.97万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582156
关键词：
Actomyosin Anaphase Animals Antineoplastic Agents Behavior Binding Biochemical Biophysics Blood Cells Cell Cycle Cell Shape Cell division Cell membrane Cells Cellular biology Chromatin Collection Contracts Coupled Crosslinker Cues Cytokinesis Cytoskeletal Modeling Cytoskeleton Development Disease Drug Targeting Ensure F-Actin Family Feedback Fiber Filament Gastrointestinal tract structure Generations Genome Genome Stability Grain Heterogeneity Lead Length Malignant Neoplasms Mechanics Meiosis Methods Microfilaments Microscope Mitotic Modeling Myosin Type II Neutropenia Organism Pattern Persons Regulation Research Role Shapes Signal Transduction Skin Sum Time Tissues Work anillin base cancer cell crosslink daughter cell depolymerization falls in vivo innovation mathematical model membrane polarity millisecond nanoscale non-muscle myosin particle programs recruit spatiotemporal theories tumor zygote

项目摘要

Project Summary Cytokinesis is the physical division of one cell into two. This final step of the mitotic or meiotic cell cycle partitions the duplicated and segregated genome into topologically distinct daughter cells, and thus ensures genome stability. Cytokinesis is essential for development of the fertilized egg into a multicellular organism, for the replenishment of tissues to compensate for wear and tear, and to avoid diseases of proliferation including cancer and some neutropenias (blood cell disorders). For over a century, people have marveled through the microscope at dividing animal cells, but major questions about the mechanisms of cytokinesis remain. Many of these questions fall under the three Themes of our research program: 1) the cytoskeletal rearrangements that drive contractility, 2) the role of feedback loops in cytokinetic regulation, and 3) modeling the mesoscale. In animal cytokinesis, the cell changes shape as a furrow forms at the cell equator, the region between the two masses of segregated chromatin, as defined by spatio-temporal cues from the anaphase spindle. These cues lead to local activation of RhoA at the plasma membrane. RhoA elicits non-muscle myosin II (NMMII) filament assembly and activity, the generation of long actin filaments (F-actin) by formins, and the cortical recruitment of crosslinkers including anillin and septins. In sum, a circumferential band of cortical actomyosin cytoskeleton assembles and contracts via rearrangement of these cytoskeletal components. F-actin is slid, bundled, crosslinked and coupled to the plasma membrane, polarity sorted, bent, broken and depolymerized. The biophysics of many nano-scale binding partnerships are well studied, but often with sparse collections and without confinement. Since the relative contributions of the many activities listed above to in vivo network dynamics are unknown, our first theme is to define the cytoskeletal remodeling that underlies contractility. After spindle cues pattern the cell equator, both biochemical and mechanical positive feedback boosts these signals. Concurrently, global and localized inhibition via negative feedback limits RhoA activity. Our unpublished observations of contractile oscillations suggest that multiple negative feedback loops coexist. The second theme of our work is the role of feedback loops in cytokinetic regulation. To develop a conceptual model of cytoskeletal rearrangements in cell division, one may imagine the nanoscale molecules and fibers and their millisecond behaviors literally woven into a dynamic material. Like biophysics and cell biology, respectively, mathematical modeling also describes cytoskeletal rearrangements at these two ends of the time- and length scales, via distinct approaches: particle-based modeling (nano- or micro- scale), or continuum mechanics theory (macro-scale). Since both families of approaches have limited ability to coarse grain the mesoscale spatial and temporal heterogeneities of the cytokinetic ring components’ activity states, behaviors, abundances, and combinations, we are working to understand cytokinetic cytoskeletal rearrangements and integrated regulation, by innovating methods to model the mesoscale (theme three).

项目概要细胞分裂是一个细胞一分为二的物理分裂，这是有丝分裂或减数分裂细胞周期的最后一步。将复制和分离的基因组划分为拓扑不同的子细胞，从而确保基因组稳定性对于受精卵发育成多细胞生物至关重要。补充组织以补偿磨损，并避免增殖性疾病，包括一个多世纪以来，人们一直对癌症和某些中性粒细胞减少症（血细胞疾病）感到惊讶。显微镜观察动物细胞分裂，但关于胞质分裂机制的许多主要问题仍然存在。这些问题属于我们研究计划的三个主题：1）细胞骨架重排驱动收缩性，2）反馈回路在细胞因子调节中的作用，以及3）中尺度建模。在动物胞质分裂中，细胞改变形状，在细胞赤道（细胞赤道之间的区域）处形成皱纹。分离的染色质的两个质量，由后期纺锤体的时空线索定义。信号导致质膜上 RhoA 的局部激活，从而引发非肌肉肌球蛋白 II (NMMII)。肌动蛋白丝的组装和活性、福尔明产生的长肌动蛋白丝（F-肌动蛋白）以及皮质包括苯胺和脓毒蛋白在内的交联剂的募集总之，是皮质肌动球蛋白的圆周带。细胞骨架通过这些细胞骨架成分的重排进行组装和收缩，与质膜成束、交联和偶联，极性分类、弯曲、断裂和解聚。许多纳米级结合伙伴关系的生物物理学已得到充分研究，但通常收集稀疏且由于上面列出的许多活动对体内网络的相对贡献。动力学是未知的，我们的第一个主题是定义收缩性基础的细胞骨架重塑。在纺锤体提示形成细胞赤道后，生化和机械正反馈都会增强同时，通过负反馈进行的全局和局部抑制限制了我们的 RhoA 活性。未发表的收缩振荡观察结果表明，多个负反馈回路并存。我们工作的第二个主题是反馈环在细胞因子调节中的作用。为了开发细胞分裂中细胞骨架重排的概念模型，人们可以想象纳米级分子和纤维及其毫秒行为实际上编织成动态材料。分别在生物物理学和细胞生物学中，数学模型还描述了细胞骨架重排时间和长度尺度的两端，通过不同的方法：基于粒子的建模（纳米或微米）尺度）或连续介质力学理论（宏观尺度），因为这两种方法的能力都有限。粗颗粒细胞因子环成分活性的中尺度空间和时间异质性状态、行为、丰度和组合，我们正在努力了解细胞因子细胞骨架通过创新方法来模拟介尺度（主题三），进行重新排列和综合调控。