Project 2: Comparative and Functional Genomics Analysis of Superfund Toxicants

项目2：超级基金毒物的比较和功能基因组学分析

• 批准号: 8833293
• 负责人: PAUL RUSSELL
• 金额: $ 28.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833293
• 关键词: Acute; Affect; Arabidopsis; Arsenic; Biological; Biological Assay; Bone Diseases; Cadmium; Camping; Candidate Disease Gene; Cardiovascular Diseases; Cells; Child; Chromium; Cluster Analysis; Communities; Complement; Complex; DNA Damage; Data; Detection; Diploidy; Eukaryota; Exposure to; Fission Yeast; Foundations; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Glean; Goals; Haploidy; Health; Heavy Metals; Human; Individual; Infertility; Instruction; Kidney; Laboratory Organism; Lead; Metal exposure; Mexico; Modeling; Nickel; Organism; Pathway interactions; Poisoning; Population; Predisposition; Proteins; Proteomics; RNA Interference; Relative (related person); Reporter; Research; Resistance; Resources; Rivers; Role; Saccharomyces cerevisiae; Saccharomycetales; Site; Solid; Source; Stress; Superfund; Technology; Testing; Toxic Environmental Substances; Toxicant exposure; Toxicogenomics; Toxicology; Translational Research; Variant; cancer type; comparative; comparative genomics; deep sequencing; deletion library; functional genomics; in utero; insight; liver injury; mutant; nervous system disorder; programs; research study; response; stress activated protein kinase; superfund site; toxicant; transcription factor

Project 2 will use functional toxicogenomics and proteomics technologies to uncover the genes and pathways that determine cellular responses and genetic susceptibilities to arsenic, cadmium, chromium, nickel and other heavy metals that contaminate Superfund sites. Comparative functional genomics will provide key insights into some of the basic mechanisms that determine resistance or sensitivity to heavy metal toxicants. These studies are divided into three Specific Aims: 1) Assemble a functional genomic profile of fission yeast using a panel of environmental toxicants assessed with haploid and diploid deletion libraries. Barcode analysis determined by deep sequencing will provide a detailed and quantitative picture of the genes that determine susceptibilities to heavy metals. Cluster analysis will be applied to toxicants tested in pure forms or in mixtures. 2) Build on the functional genomic profiling data by assembling epistatic miniarray profiles (E-MAPs). These mutant interaction studies will define the genetic networks that determine cellular sensitivities to heavy metals and may uncover interactions with other pathways such as DNA damage responses (DDRs). The existence of conserved genetic interactions in human cells will be assessed by RNAi analyses. 3) Investigate changes in protein abundance triggered by heavy metal exposure using isobaric tag for relative and absolute quantitation (iTRAQ). These proteomic studies will provide further insights into how stress-regulated transcription factors and stress-activated protein kinases control cellular responses to heavy metal stress.

项目2将使用功能性毒理学和蛋白质组学技术来揭示基因和 确定细胞反应和对砷，镉，铬的遗传敏感性的途径， 镍和其他污染超级基金地点的重金属。比较功能基因组学将 对确定对沉重的抵抗力或敏感性的一些基本机制提供关键见解 金属有毒物质。 这些研究分为三个具体目标： 1）使用评估的环境有毒物质组装裂变酵母的功能基因组谱 带有单倍体和二倍体缺失库。通过深度测序确定的条形码分析将提供 确定重金属敏感性的基因的详细和定量图片。簇 分析将应用于以纯形或混合物中测试的有毒物质。 2）通过组装上皮的Miniarray概况（E-MAPS）来建立功能基因组分析数据。这些 突变相互作用研究将定义确定细胞敏感性重量的遗传网络 金属并可能发现与其他途径（例如DNA损伤反应（DDR））的相互作用。这 人类细胞中保守的遗传相互作用的存在将通过RNAi分析评估。 3）调查使用同种异性标签重金属暴露触发蛋白质丰度的变化 相对和绝对定量（ITRAQ）。这些蛋白质组学研究将提供进一步的见解 压力调节的转录因子和应激激活的蛋白激酶控制对重的细胞反应 金属应力。