The Genetic Determinants of Differential Phosphoproteome Response to DNA Damage

磷酸化蛋白质组对 DNA 损伤反应差异的遗传决定因素

• 批准号: 8984007
• 负责人: Brett Warren Engelmann
• 金额: $ 2.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2015-11-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984007
• 关键词: Address; Aftercare; Age; Aging; Alkylating Agents; Automobile Driving; Cardiovascular Diseases; Cell Cycle Checkpoint; Cell Line; Cell model; Cells; Chromosome Mapping; Clinical; Co-Immunoprecipitations; Code; Communication; Complement; Coupled; DNA; DNA Damage; DNA Repair; DNA lesion; Dacarbazine; Data; Detection; Disease; Endogenous Factors; Environment; Environmental Impact; Environmental Policy; Exogenous Factors; Exposure to; Gene Expression Regulation; Genetic; Genetic Determinism; Genetic Markers; Genetic Variation; Genetic study; Genome; Genotype; Goals; Human; Human Genome; Incidence; Individual; Investigation; Joints; Knowledge; Link; Liquid Chromatography; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Mutation; Neurodegenerative Disorders; Pathway interactions; Penetrance; Pharmaceutical Preparations; Phenotype; Phosphopeptides; Phosphoproteins; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Population; Post-Translational Protein Processing; Proteins; Proteomics; Public Health; Quantitative Trait Loci; Regulator Genes; Relative (related person); Research; Risk; Role; Sampling; Signal Transduction; Stable Isotope Labeling; Stimulus; Untranslated RNA; Variant; Work; cancer therapy; carcinogenesis; chemotherapy; environment related cancer; genetic variant; genome editing; genome wide association study; improved; lymphoblast; mRNA Expression; personalized medicine; programs; public health relevance; response; risk variant; tandem mass spectrometry; trait

 DESCRIPTION (provided by applicant): Each cell in our body is constantly exposed to a myriad of endogenous and exogenous factors that result in the accumulation of thousands of diverse DNA lesions per day. DNA damage is a causative factor in aging and carcinogenesis and plays a critical role in many disorders such as neurodegenerative and cardiovascular disease. Inter-individual variation in sensitivity to DNA damage is significant, with profound ramifications for cancer incidence and treatment, ageing, and public health in general. The damage response (DDR) is the concerted cellular program that mitigates the effects of DNA damage by integrating many damage detection, signaling and cell cycle checkpoint proteins with various DNA repair mechanisms. The majority of the signaling between DDR components is mediated at the post-translational level through phosphorylation. Currently, we have identified very few of the genetic variants driving differential sensitivity to DNA damage and know very little about their DDR context specific mechanisms. Addressing these questions will have direct and immediate application within a personalized medicine framework. The proposed research will identify regions of the genome that correlate with inter-individual variation in response to DNA damage at the post-translational penetrance level. Cells derived from fully sequenced individuals will be subject to quantitative phosphoproteomic analysis before and after DNA damage. Using a quantitative trail locus (QTL) mapping approach, genetic variants associated with differential phosphopeptide levels and sensitivity to DNA damage will be identified. Using the DDR as a guide, a limited subset of QTLs will be characterized to identify their mode of action.

 描述（由申请人提供）：我们体内的每个细胞不断暴露于无数的内源性和外源性因素，导致每天积累数千种不同的DNA损伤。DNA损伤是衰老和癌症发生的一个致病因素，在许多疾病如神经退行性疾病和心血管疾病中起着关键作用。个体间对DNA损伤的敏感性差异很大，对癌症的发病率和治疗、老龄化和一般公共卫生都有深远的影响。损伤反应（DDR）是一种协同的细胞程序，它通过整合许多损伤检测、信号传导和细胞周期检查点蛋白与各种DNA修复机制来减轻DNA损伤的影响。DDR组分之间的大部分信号传导通过磷酸化在翻译后水平介导。目前，我们已经确定了很少的遗传变异驱动差异敏感性DNA损伤和知道很少关于他们的DDR上下文特定的机制。解决这些问题将在个性化医疗框架内直接和立即应用。这项拟议中的研究将确定与个体间变异相关的基因组区域，这些变异是在翻译后转录水平上对DNA损伤的反应。在DNA损伤之前和之后，将对来自完全测序个体的细胞进行定量磷酸蛋白质组学分析。使用定量跟踪基因座（QTL）作图方法，将鉴定与差异磷酸肽水平和对DNA损伤敏感性相关的遗传变异。使用DDR作为指导，将表征QTL的有限子集以鉴定其作用模式。