DNA Damage Networks

DNA损伤网络

• 批准号: 8181035
• 负责人: MICHAEL B YAFFE
• 金额: $ 34.98万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-30 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181035
• 关键词: Apoptosis; Biology; Breast Cancer Cell; Cancer Model; Cell Culture System; Cell Cycle Arrest; Cells; Chemical Models; Clinical; Combined Modality Therapy; Computer Simulation; Critical Pathways; DNA Damage; DNA Repair; Data; Drug Combinations; Epidermal Growth Factor Receptor; Experimental Models; Funding; Genotoxic Stress; Goals; Human; In Vitro; Lymphoma; Malignant Neoplasms; Modeling; Molecular; Monitor; Mus; Patients; Phenotype; Predisposition; Protein Kinase; Resistance; Signal Pathway; Signal Transduction; System; Systems Biology; Testing; Therapeutic; Time; Transcriptional Regulation; Work; Xenograft procedure; base; cancer therapy; cell killing; improved; insight; mathematical model; neoplastic cell; research study; response; senescence; therapeutic target; tumor

The long-term goal of this project is to develop mathematical and physico-chemical models that describe the cellular response to DNA damage at the network and systems biology level. The work involves the tight integration of focused rigorously quantitative experimental studies monitoring the activity of a large number of intracellular protein kinase signaling pathways and correlating their activity with the cellular phenotypes of DNA damage-induced cell cycle arrest and re-entry, apoptosis or senescence using a variety of quantitative mathematical models. These models capture the relevant signaling information, and provide new insights into the underlying biology. Experiments focus on human lymphoma and breast cancer cells with direct translational relevance, and build directly on our prior experimental and modeling work performed during the previous funding period. In lymphoma cells our focus includes t h e connection between DNA damage signaling, cellular response, and transcriptional regulation since our preliminary data suggests that transcriptional changes are likely to be especially important in predicting the response of this tumor type to treatment. In breast cancer cells, we focus on t h e interactions and cross-talk between the EGFR and DNA damage signaling pathways, since our preliminary data suggests that these signals can b e manipulated advantageously to enhance tumor cell killing using agents that are currently in wide clinical use. The computational models that result from this work illuminate which components of the various signaling pathways are most important for the different cellular responses at various times after the genotoxic stress, thereby defining the critical pathways through which cellular signaling information flows. Predictions from the models for both of these tumor types are then explored and tested at a variety of scales, including in vitro cell culture systems, murine xenografts, and mouse cancer models. Guided by t h e models, key nodes in the signaling pathways implicated as being critically important at particular time points after DNA damage will be identified, providing a mechanistic molecular basis underlying the observed cellular phenotype induced by genotoxic stress. The result of these experiments will be a significantly enhanced understanding of the global DNA damage response at the systems level including mechanisms underlying cancer predisposition and therapeutic resistance, and the identification of critical signaling pathways and molecules that should be targets for therapeutic manipulation in cancer treatment.

该项目的长期目标是开发数学和物理化学模型，在网络和系统生物学水平上描述细胞对 DNA 损伤的反应。这项工作涉及紧密整合重点严格定量的实验研究，监测大量细胞内蛋白激酶信号通路的活性，并将其活性与 DNA 损伤诱导的细胞周期停滞和重新进入、细胞凋亡或衰老的细胞表型相关联，使用多种定量数学模型。这些模型捕获相关信号信息，并提供新的见解 进入基础生物学。实验重点关注具有直接转化相关性的人类淋巴瘤和乳腺癌细胞，并直接建立在我们之前资助期间进行的实验和建模工作的基础上。在淋巴瘤细胞中，我们的重点包括 DNA 损伤信号、细胞反应和转录调控之间的联系，因为我们的初步数据表明转录变化可能对于预测这种肿瘤类型对治疗的反应特别重要。在乳腺癌细胞中，我们重点关注 EGFR 和 DNA 损伤信号通路之间的相互作用和串扰，因为我们的初步数据表明，可以使用目前广泛临床使用的药物来有利地操纵这些信号，以增强肿瘤细胞杀伤力。这项工作产生的计算模型阐明了各种信号传导途径的哪些成分对于基因毒性应激后不同时间的不同细胞反应最重要，从而定义了细胞信号传导信息流动的关键途径。预测来自 然后，对这两种肿瘤类型的模型进行了各种规模的探索和测试，包括体外细胞培养系统、鼠异种移植物和小鼠癌症模型。在模型的指导下，将识别出在 DNA 损伤后特定时间点至关重要的信号通路中的关键节点，从而为观察到的由基因毒性应激诱导的细胞表型提供了机制分子基础。这些实验的结果将显着增强对系统水平上的整体 DNA 损伤反应的理解，包括癌症易感性和治疗耐药性的机制，以及识别关键信号通路和分子，这些通路和分子应该成为癌症治疗中治疗操作的目标。