Asynchronous mitosis in multinucleate cells

多核细胞的异步有丝分裂

• 批准号: 7984978
• 负责人: Amy Susanne Gladfelter
• 金额: $ 29.62万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984978
• 关键词: Biological Models; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cell Signaling Process; Cell physiology; Cells; Cyclins; Cytoplasm; Data; Diffusion; Disease; Environment; Exhibits; Fluorescence; Genetic Transcription; Giant Cells; Heterogeneity; Individuality; Inequality; Knowledge; Learning; Life; Mammals; Measures; Mitosis; Modeling; Molds; Molecular; Molecular Genetics; Movement; Noise; Nuclear; Organism; Pathogenesis; Pathology; Pharmacological Treatment; Photobleaching; Population; Positioning Attribute; Process; Proteins; Signal Transduction; Sister; Source; Spectrum Analysis; Staging; Statistical Models; System; Testing; Time; Transcript; Translating; Variant; Work; Yeasts; base; cell behavior; cell growth; cellular imaging; cyclin G1; design; heterokaryon; mathematical model; mutant; neoplastic cell; non-genetic; programs; public health relevance; research study; time use; trait

DESCRIPTION (provided by applicant): In organisms ranging from single-celled yeasts to mammals, genetically identical cells exhibit variable cell division cycle times even when growing in the same environment. The sources and benefits of variability in a process such as the cell cycle that is wired for accuracy are unknown. In particular, it is not understood whether cell cycle timing variability is purely stochastic or whether it may be regulated as part of the design of cell cycle circuits. Variability in other cell processes has been shown to be beneficial, so cell cycle variability may in fact be an adaptive trait. The multinucleate, filamentous fungus, Ashbya gossypii, is a unique model system to study cell cycle timing variability because nuclei divide asynchronously within a common cytoplasm. Such asynchrony in a syncytium requires variable timing and nuclear autonomy in cell cycle signaling. As all proteins are translated in a common cytoplasm, it is mysterious how multiple, out of sync, cell cycle oscillators can coexist. We are taking advantage of the asynchronous division cycle in this model system to discover whether variability is programmed into the cell cycle and to learn how nuclear autonomy can be established. Knowledge of the molecular basis for variability is necessary for a complete understanding of cell cycle control and the pathologies influenced by a misregulated cell cycle. Population level variability in cell cycle decisions can impact processes as diverse as fungal pathogenesis and tumor cell behavior, and may be a factor influencing the efficacy of pharmacological treatments. While some cell-to-cell variability can be attributed to molecular noise in transcription, it is certain that other, as yet unidentified, cellular reservoirs of non-genetic individuality exist. In this proposal, we combine live cell imaging with computational and molecular genetic approaches to identify sources of variability in the cell cycle and determine how nuclear autonomy is established. With this model fungal system, we are well positioned to identify conserved sources of cell cycle variability and learn how cell signaling processes can be insulated within a common cytoplasm. The specific aims of the project are: 1) To determine whether variability in G1 duration is stochastic or regulated. 2) To test the hypothesis that nuclear size controls cell cycle timing and variability. 3) To test the hypothesis that spatially restricted protein movement creates nuclear autonomy. Timing variability exists in nearly all cell division cycles and knowing the basis of heterogeneity is essential for a complete understanding of the cell cycle. In this project, we will determine if timing variability is programmed in the cell division cycle, learn how nuclear size controls timing and how the cytoplasm can be functionally compartmentalized to maintain asynchrony. PUBLIC HEALTH RELEVANCE: In organisms ranging from single-celled yeasts to mammals, genetically identical cells take different amounts of time to divide even when growing in the same environment. This cell-to-cell variability in division timing can impact processes as diverse as fungal pathogenesis and tumor cell growth, and may be a factor influencing the efficacy of pharmacological treatments. In this work we will identify molecular sources of timing variability that will have relevance to the diverse diseases influenced by a misregulated cell division cycle.

描述（由申请人提供）：在从单细胞酵母到哺乳动物的生物中，遗传相同的细胞即使在同一环境中生长也会显示出可变的细胞分裂周期时间。在诸如细胞周期之类的过程中的可变性的来源和益处是未知的。特别是，尚不理解细胞周期定时变异性是否纯粹是随机性，还是可以作为细胞周期电路设计的一部分进行调节。其他细胞过程的变异性已被证明是有益的，因此细胞周期的变异实际上可能是一种适应性特征。多核，丝状真菌，Ashbya Gossypii是一个独特的模型系统，可以研究细胞周期时机变异性，因为核在共同的细胞质中异步分裂。在合胞体中的异步需要在细胞周期信号传导中变化的时间和核自主权。由于所有蛋白质均以常见的细胞质翻译，因此神秘的多个蛋白质是神秘的，不同步，细胞循环振荡器可以共存。我们正在利用该模型系统中的异步分裂周期，以发现是否将可变性编程到细胞周期中并了解如何建立核自主权。对可变性的分子基础的了解对于完全了解细胞周期控制和受细胞周期不正常的病理的理解是必要的。细胞周期决策中的种群水平变异性会影响像真菌发病机理和肿瘤细胞行为一样多样化的过程，并且可能是影响药理治疗功效的因素。虽然某些细胞间的可变性可以归因于转录中的分子噪声，但可以肯定的是，尚未确定的其他非遗传个性的细胞库存在。在此提案中，我们将活细胞成像与计算和分子遗传方法相结合，以识别细胞周期中可变性的来源，并确定如何建立核自主权。使用此模型真菌系统，我们可以很好地确定细胞周期变异性的保守来源，并了解如何在常见的细胞质中绝缘细胞信号传导过程。该项目的具体目的是：1）确定G1持续时间的变异性是随机或调节的。 2）测试核大小控制细胞周期时机和可变性的假设。 3）检验以下假设，即在空间限制的蛋白质运动会产生核自主权。几乎所有细胞分裂循环中都存在定时变异性，并且了解异质性的基础对于完全了解细胞周期至关重要。在该项目中，我们将确定是否在细胞分裂周期中编程了定时变异性，了解核大小如何控制时间以及如何在功能上划分的细胞质以维持异步。 公共卫生相关性：在从单细胞酵母到哺乳动物的生物中，遗传相同的细胞即使在同一环境中生长也需要不同的时间来分裂。分裂时序中的这种细胞间变异性会影响像真菌发病机理和肿瘤细胞生长一样多样化的过程，并且可能是影响药理治疗功效的因素。在这项工作中，我们将确定定时变异性的分子来源，这将与受细胞分裂周期不正调的各种疾病相关。