Dynamics of Signaling Pathways: Mechanism and Function

信号通路的动力学：机制和功能

• 批准号: 8840265
• 负责人: Galit Lahav
• 金额: $ 39.55万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840265
• 关键词: Affect; Apoptosis; Behavior; Bioinformatics; Biological; Biological Assay; Cancerous; Cell Fate Control; Cells; Cessation of life; Collaborations; Computer Analysis; DNA Damage; DNA Repair; Data; Decision Making; Development; Disease; Drug effect disorder; Event; Fluorescence; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Growth; Health; Human; In Vitro; Individual; Knowledge; Lead; Life; Link; Malignant Neoplasms; Maps; Measurement; Modeling; Molecular; Molecular Biology; Mutate; Mutation; Outcome; Output; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Play; Protein p53; Proteins; RNA Interference; Regulation; Regulator Genes; Reporter; Role; Series; Signal Pathway; Signal Transduction; Stress; System; Time; Translating; Tumor Suppressor Proteins; base; cancer cell; cellular imaging; chemotherapy; experimental analysis; feeding; insight; irradiation; mathematical model; mutant; novel strategies; promoter; prototype; response; senescence; transcription factor; tumor

DESCRIPTION (provided by applicant): Our long-term goal is to understand how the dynamic behavior of biological signals is controlled and how these dynamics affect cellular responses. This proposal focuses on fundamental cellular mechanisms of the p53 signaling network. The p53 system orchestrates cellular responses to environmental insult and spontaneous damage, particularly those that damage DNA. Loss or mutation of the p53 system strongly predisposes human cells to cancer, and is observed in a large fraction of cancers. While the molecular function and regulation of the p53 pathway has been extensively investigated, exactly how wild-type or mutant p53 determines the fate of individual cells, and why cells exposed to the same insult end up having different fates, is poorly understood. Answering these questions requires a quantitative understanding of the order of events in single cells and the causal relationships between cellular background (cancer and non-cancerous cells), p53 status (wild-type or mutated), p53 dynamics and cellular outcomes (growth, arrest or death). We hypothesize that the temporal dynamics of p53 (i.e. changes in the levels of p53 over time) plays a role in cell fate decisions: we have recently shown that different stresses lead to different p53 dynamics and that modulation of p53 dynamics alters cellular outcomes. In this grant we propose to combine quantitative dynamic measurements of p53 and cellular outcomes in single cells (using live cell imaging) with mathematical modeling and manipulation of the p53 circuit to determine the molecular mechanisms that link p53 dynamics to specific phenotypic outcomes. We will also investigate the effect of mutations in the p53 network on p53 dynamics and on cell fate decisions and how p53 dynamics and downstream decision-making respond to representative genotoxic chemotherapy drugs. Our results will provide new insights into the control and manipulation of the p53 pathway, perhaps the most important pathway protecting human cells against the development of cancer. We anticipate that a detailed quantitative understanding of the p53 circuit, the key circuit controlling the decision to grow or die in single cells, will helpus understand why some cells die in response to chemotherapeutic drugs while others survive, and may suggest novel strategies to selectively push cancer cells toward permanent arrest or death. It addition, our study will be help predict the effects of specific drugs on tumors with specific genotypes and will provide a prototype for the analysis, description, and understanding of the dynamics of other signaling pathways in human cells.

描述（由申请人提供）：我们的长期目标是了解如何控制生物信号的动态行为以及这些动态如何影响细胞反应。该建议重点是p53信号网络的基本细胞机制。 p53系统策划了细胞对环境侮辱和自发损害的反应，尤其是损害DNA的损害。 p53系统的丧失或突变极容易使人类细胞患癌症，并且在很大一部分癌症中观察到。虽然已经对p53途径的分子功能和调节进行了广泛的研究，但野生型或突变体p53的准确是如何确定单个细胞的命运，以及为什么暴露于同一侮辱的细胞最终会产生不同的命运，而对此则知之甚少。回答这些问题需要定量了解单个细胞中事件的顺序以及细胞背景（癌症和非癌细胞），p53状态（野生型或突变），p53动力学和细胞结果（生长，停滞或死亡）之间的因果关系。我们假设p53的时间动力学（即随着时间的推移p53水平的变化）在细胞命运决策中起作用：我们最近表明，不同的应力会导致不同的p53动力学，并且p53动力学的调节改变了细胞的结果。在这笔赠款中，我们建议将p53和单个细胞中细胞结局的定量动态测量（使用活细胞成像）与p53电路的数学建模和操纵结合，以确定将p53动力学连接到特定表型的分子机制。我们还将研究p53网络中突变对p53动力学以及细胞命运决策的影响，以及p53动力学和下游决策如何对代表性的遗传毒性化学疗法药物做出反应。我们的结果将为p53途径的控制和操纵提供新的见解，这可能是保护人类细胞免受癌症发展的最重要途径。我们预计，对p53电路的详细定量理解，控制单个细胞中生长或死亡的关键电路将帮助人们理解为什么某些细胞会在化学治疗药物中死亡，而另一些细胞可以生存，并可能建议选择新的策略，以选择性地将癌细胞推向永久性停滞或死亡。此外，我们的研究将有助于预测特定药物对具有特定基因型的肿瘤的影响，并将为人类细胞中其他信号通路的动力学分析，描述和理解提供原型。