Discovery of Gene Regulatory Networks Controlling Cell Cycle Exit in Drosophila,

发现果蝇中控制细胞周期退出的基因调控网络，

• 批准号: 7422084
• 负责人: Mingzhou Song
• 金额: $ 8.12万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422084
• 关键词: Animal Model; Biological Models; Cell Cycle; Cell Cycle Regulation; Choristoma; Computer Simulation; Computer software; Coupled; Cultured Cells; Data; Development; Drosophila genus; Drosophila melanogaster; Ensure; Gene Expression; Genetic; Insecta; Investigation; Lead; Link; Methodology; Modeling; Mus; Nature; Pilot Projects; Process; Regulator Genes; Signal Transduction; System; Systems Biology; Testing; Wing; abstracting; cdc Genes; extracellular; gene discovery; in vivo; novel; positional cloning; research study; tumorigenesis

ABSTRACT Terminal cellular differentiation is often coupled with a halt in proliferation and permanent exit from the cell cycle. A loss of coordination between these processes can lead to aberrant tissue development and tumorigenesis. Despite its importance, little is known about how cell cycle exit and terminal differentiation are coordinated. One hypothesis, supported by studies in cell culture, mice and insects, suggests that the extracellular signals that trigger differentiation also control the expression of key cell cycle regulators. However, the identities of these regulators and the genetic regulatory networks linking extracellular differentiation signals with cell cycle genes remain largely unknown. To identify the gene regulatory networks linking terminal differentiation with cell cycle exit in vivo, this collaborative pilot project between Dr. Edgar at FHCRC and Dr. Song at NMSU proposes to combine a novel systems biology approach through discrete dynamic system models with high throughput temporal gene expression and reverse genetics studies in the successful model organism, Drosophila melanogaster. These models will allow one to predict genetic networks that connect extracellular signals with the cell cycle machinery. The models will be tested and explored by experiments in vivo. This project has three specific aims: Aim 1. To advance the methodology and software to generate discrete dynamic system models from genomewide temporal gene expression. Microarray data from Drosophila wings will be used. Aim 2. To test the modeling approach by genetic perturbations in silico and comparing the predicted changes in gene expression to the changes experimentally observed in vivo. Aim 3. To use the modeling approach to predict new genetic regulatory networks converging on cell cycle control during differentiation, and experimentally explore and validate the predicted networks in vivo. Importantly, the aims are highly iterative and will lead to a close integration and cooperation between the in vivo experiments at FHCRC and in silico modeling at NMSU. These investigations will ultimately provide information about how developmental signals interface with the cell cycle to ensure cell cycle exit upon terminal differentiation. In addition, a powerful and widely applicable computational approach to elucidating gene regulatory networks will be developed.

摘要 细胞的终末分化通常伴随着细胞增殖的停止和永久退出。 周而复始。这些过程之间的协调缺失可能会导致组织发育异常和 肿瘤发生学。尽管它很重要，但人们对细胞周期退出和末端分化是如何进行的知之甚少 协调一致。一种假说得到了对细胞培养、老鼠和昆虫的研究的支持，认为 触发分化的细胞外信号也控制着关键的细胞周期调节因子的表达。然而， 这些调控因子的身份和连接细胞外分化信号的遗传调控网络 关于细胞周期，基因在很大程度上仍然未知。识别连接末端的基因调控网络 随着体内细胞周期的存在，FHCRC的埃德加博士和Dr。 NMSU的宋建议通过离散动态系统将一种新的系统生物学方法结合起来 高通量时间基因表达模型和成功模型中的反向遗传学研究 有机体，黑腹果蝇。这些模型将使人们能够预测连接到 细胞外信号与细胞周期机制。这些模型将通过实验进行测试和探索 活着。该项目有三个具体目标： 目标1.发展从全基因组生成离散动态系统模型的方法和软件 时间基因表达。将使用来自果蝇翅膀的微阵列数据。 目的2.对遗传扰动建模方法进行验证，并对预测结果进行比较 在体内实验中观察到基因表达的变化。 目的3.用建模方法预测新的遗传调控网络收敛于细胞周期 在分化过程中进行控制，并在体内实验探索和验证预测的网络。 重要的是，这些目标是高度迭代的，并将导致在 FHCRC的活体实验和NMSU的计算机模拟。这些调查最终将提供 有关发育信号如何与细胞周期相互作用以确保细胞周期退出的信息 末端分化。此外，一种强大和广泛适用的计算方法来阐明 建立基因调控网络。