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Environmental Regulation of Cellular Responses to DNA Damage

细胞对 DNA 损伤反应的环境调节

基本信息

批准号：
9894804
负责人：
Michael Jungho Lee
金额：
$ 35.18万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-09 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894804
关键词：
Address Apoptosis Apoptosis Regulation Gene Apoptotic Biochemical Genetics Biological Assay CASP1 gene CRISPR/Cas technology Caspase Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell Line Cell physiology Cells Cessation of life Co-Immunoprecipitations Coculture Techniques Cytokine Signaling DNA Binding DNA Damage DNA Repair DNA Repair Enzymes Data Death Rate Defect Disease Drug usage Effectiveness Eligibility Determination End Point Assay Enzyme Activation Epithelial Cells Event Exposure to Family Fluorescence Microscopy Genes Genetic Screening Genomics Genotoxic Stress Goals Health Homo Human Immune Infection Inflammasome Inflammatory Knock-out Lead Life Malignant Neoplasms Measures Modeling Monitor Nerve Degeneration Outcome Outcome Study Phase Phenotype Phosphotransferases Physiology Premature aging syndrome Process Protein Array Proteins Proteomics Regulatory Pathway Signal Pathway Signal Transduction Signaling Protein Specificity Statistical Models System TP53 gene Testing Tissues cancer cell cell growth regulation chemical genetics design experimental study fitness genetic regulatory protein genetically modified cells genome-wide improved live cell microscopy member paracrine protein complex public health relevance recruit repaired response screening sensor

项目摘要

SUMMARY The overarching goal of this project is to understand how the DNA Damage Response (DDR) activates apoptotic cell death. The DDR is a kinase driven signaling pathway that coordinates multiple cellular functions, including: surveillance for DNA damage, recruitment of DNA repair enzymes, and activation of cell cycle checkpoint arrest. Collectively, these events promote survival following genotoxic stress. Alternatively, in some cases the DDR activates apoptosis. Although much is known about these each of these functions, it still remains unclear why activation of the DDR leads to survival in some cases and death in others. The current model suggests that p53 controls the decision to arrest and repair, or alternatively, to activate cell death. This model does not explain the common observation that cancer cells – which often lack p53 – can robustly activate apoptosis when exposed to DNA damage. Thus, other unidentified mechanisms must also exist to facilitate DDR-induced cell death. Our strategy for identifying mechanisms by which the DDR activates apoptosis was to perform functional genetic screens in cells that lack p53 but retain high levels of DNA damage sensitivity. Our screen has identified that activation of caspase-1 and caspase-1 associated inflammatory cytokine signaling is required for robust DNA damage induced cell death. This was unexpected because unlike other members of the caspase family, caspase-1 is not thought to contribute to apoptotic cell death. In this proposal, we will use live cell microscopy experiments to determine the fate of cells that have activated caspase-1. Additionally, we will use biochemical and genetic experiments to determine mechanisms by which caspase-1 is activated by DNA damage. Finally, we will use high-throughput targeted proteomic and genomic analyses, together with data driven statistical modeling, to determine mechanisms by which caspase- 1 signaling is integrated with the DDR to promote apoptotic cell death. A major outcome from this study will be an understanding of how intra-cellular and inter-cellular crosstalk between inflammatory and DDR signaling helps to facilitate activation of apoptosis. This information may help to understand the variable sensitivity to DNA damage that is observed across tissues and across people, and may ultimately improve our ability to reliably control life-death decisions following DNA damage.

总结