Understanding the robustness of cell cycles

了解细胞周期的稳健性

• 批准号: 10587456
• 负责人: Qiong Yang
• 金额: $ 29.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587456
• 关键词: Adult; Architecture; Bacteria; Biochemical; Biological Pacemakers; Biological Process; Biology; Cell Cycle; Cell Nucleus; Cell division; Cell physiology; Cell-Free System; Cells; Circadian Rhythms; Comparative Study; Complex; Cytoplasm; Defect; Development; Developmental Biology; Developmental Process; Devices; Discipline; Disease; Ecosystem; Embryo; Encapsulated; Environment; Feedback; Genetic; Goals; Human; Image; Impairment; Knowledge; Link; Malignant Neoplasms; Microfluidics; Mitotic; Mitotic Cell Cycle; Modeling; Modification; Molecular; Mus; Neurons; Organism; Pattern; Performance; Periodicity; Physiology; Positioning Attribute; Process; Property; Reaction; Recording of previous events; Regulation; Research; Role; Shapes; Signal Pathway; Sleeplessness; Structure; System; Systems Biology; Training; Zebrafish; computer studies; design; environmental change; experimental study; improved; innovation; insight; interest; rational design; reconstitution; resilience; response; simulation; somitogenesis; synthetic biology; theories

Project Summary Biological oscillators are essential to a variety of cyclic processes in cells and development. These include cell divisions, heartbeats, and somitogenesis. Impaired biological oscillators may cause diseases from insomnia to cancer. It is thus crucial for an oscillator to develop the ability to maintain a stable function against the changes in environmental conditions. The architecture of many oscillators is highly conserved among species, despite that the actual molecules may vary from species to species. This highlights the important role of network topology in the functions of biological oscillators. How the network structure is linked to the certain functions of biological oscillators is still an open challenging question in systems and synthetic biology. The goal of this proposal is to identify the fundamental principles underlying the robust functioning of clock networks. To achieve the goal, a systematic computational approach will be applied to analyze all topological modifications that significantly impact the robustness and tunability of clock networks. As a comparison to computational studies, this proposal will experimentally investigate the possible mechanisms by which cell cycles retain robust oscillations. The proposed experiments make use of a droplet-based microfluidic system, where cell-free extracts are encapsulated in droplets to mimic single cells that undergo mitotic cycles. This artificial cell system will be integrated with live embryo imaging and stochastic modeling, to track and analyze many single oscillators simultaneously, and thereby quantify the robustness of the mitotic cycles to environmental changes and molecular stochasticity. To study the role of network structure in the robustness of the clock, results from intact oscillators will be compared with the ones whose sub-networks are compromised. The results from the mitotic clock may apply to a broad set of other clocks that share similar topological cores. The results should also provide valuable insights on how to design a robust synthetic clock.

项目概要 生物振荡器对于细胞和发育的各种循环过程至关重要。这些包括细胞 分裂、心跳和体节发生。生物振荡器受损可能导致失眠等疾病 癌症。因此，对于振荡器来说，发展针对变化保持稳定功能的能力至关重要 在环境条件下。许多振荡器的结构在物种之间是高度保守的，尽管 实际分子可能因物种而异。这凸显了网络拓扑的重要作用 生物振荡器的功能。网络结构如何与生物的某些功能联系起来 振荡器仍然是系统和合成生物学中一个开放的具有挑战性的问题。该提案的目标是 确定时钟网络稳健运行的基本原理。为了实现这一目标，一个 将应用系统的计算方法来分析所有显着的拓扑变化 影响时钟网络的鲁棒性和可调谐性。作为与计算研究的比较，该提案 将通过实验研究细胞周期保持强劲振荡的可能机制。这 拟议的实验利用基于液滴的微流体系统，其中无细胞提取物 封装在液滴中以模拟经历有丝分裂周期的单细胞。该人造细胞系统将 与活体胚胎成像和随机建模相结合，跟踪和分析许多单个振荡器 同时，从而量化有丝分裂周期对环境变化的鲁棒性和 分子随机性。研究网络结构在时钟鲁棒性中的作用，结果来自完整的 振荡器将与其子网络受到损害的振荡器进行比较。有丝分裂的结果 时钟可以适用于共享相似拓扑核心的广泛其他时钟。结果还应提供 关于如何设计强大的合成时钟的宝贵见解。