Systems-level analysis of the regulation and function of p53 dynamics

p53 动力学调控和功能的系统级分析

• 批准号: 10262305
• 负责人: Eric Batchelor
• 金额: $ 28.59万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262305
• 关键词: Affect; Apoptosis; Behavior; Biological; Biological Assay; Cancerous; Cell Aging; Cell Cycle Arrest; Cell Death; Cells; Cellular Stress; Cellular biology; Complex; Computer Models; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Dose; Face; Gene Expression; Genes; Goals; Malignant Neoplasms; Measurement; Measures; Medicine; Mutate; Outcome; Output; Pathway interactions; Physiologic pulse; Property; Regulation; Research; Role; Series; Shapes; Stress; System; TP53 gene; Techniques; Translating; Work; chemical genetics; combat; extracellular; novel strategies; response; transcription factor; ultraviolet damage

PURPOSE: In this project, we will use a combination of computational and experimental techniques to identify the role of p53 dynamics in the regulation of important cellular stress stresses. To measure the dynamics of downstream pathways, we will make use of a suite of complementary approaches described below to assay p53 activity in both cancerous and non-transformed cellular systems. We will use chemical and genetic perturbations to alter p53 dynamics and determine the effect on p53 target gene expression and cell fate. Using computational modeling, we will integrate these data with measurements of cellular outcomes to predict pathway behavior in response to specific perturbations. By allowing us to study emergent properties that are not evident at the level of smaller-scale interactions, this type of approach will provide novel strategies for manipulating biological circuit functions, as well as generate new ways to combat cancers in which p53 dynamics are dysregulated. Progress on this project was concluded in FY20 due to the departure of Dr. Batchelor

目的：在这个项目中，我们将结合计算和实验技术来确定 p53 动力学在重要细胞应激调节中的作用。为了测量下游通路的动态，我们将利用下述的一套补充方法来测定癌性和非转化细胞系统中的 p53 活性。我们将利用化学和遗传扰动来改变 p53 动力学并确定对 p53 靶基因表达和细胞命运的影响。使用计算模型，我们将这些数据与细胞结果的测量相结合，以预测响应特定扰动的通路行为。通过让我们研究在小规模相互作用水平上不明显的新兴特性，这种方法将为操纵生物回路功能提供新策略，并产生对抗 p53 动态失调的癌症的新方法。由于 Batchelor 博士的离开，该项目的进展已于 20 财年完成

项目成果

Promoter decoding of transcription factor dynamics.

转录因子动力学的启动子解码。

• DOI: 10.1038/msb.2013.63
• 发表时间: 2013
• 期刊: Molecular systems biology
• 影响因子: 9.9
• 作者: Moody,AmieD;Batchelor,Eric
• 通讯作者: Batchelor,Eric

Using computational modeling and experimental synthetic perturbations to probe biological circuits.

• DOI: 10.1007/978-1-4939-1878-2_12
• 发表时间: 2015
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Porter JR;Batchelor E
• 通讯作者: Batchelor E

p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks.

p53以mRNA半衰期依赖性方式脉冲靶基因表达动力学多样化，并描绘了共同调节的靶基因子网。

• DOI: 10.1016/j.cels.2016.03.006
• 发表时间: 2016-04-27
• 期刊: Cell systems
• 影响因子: 9.3
• 作者: Porter JR;Fisher BE;Batchelor E
• 通讯作者: Batchelor E

Determining the Limitations and Benefits of Noise in Gene Regulation and Signal Transduction through Single Cell, Microscopy-Based Analysis.

• DOI: 10.1016/j.jmb.2017.03.007
• 发表时间: 2017-04-21
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Harton MD;Batchelor E
• 通讯作者: Batchelor E

Recent progress and open challenges in modeling p53 dynamics in single cells.

• DOI: 10.1016/j.coisb.2017.04.007
• 发表时间: 2017-06
• 期刊: Current opinion in systems biology
• 影响因子: 3.7
• 作者: Batchelor E;Loewer A
• 通讯作者: Loewer A