Alternative splicing in arsenical skin carcinogenesis
砷皮肤癌发生中的选择性剪接
基本信息
- 批准号:9979035
- 负责人:
- 金额:$ 23.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-14 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated Regions5&apos Untranslated RegionsAffectAlternative SplicingAreaArsenicArsenicalsArsenitesAttentionAutomobile DrivingBiogenesisBiologicalBiological ProcessCell Cycle RegulationCell physiologyCellsChronicChronic DiseaseComplexCountryDNA RepairDNA damage checkpointDataDiseaseEtiologyEventExposure toExpression ProfilingGene ExpressionGene Expression RegulationGenome ComponentsGlobal ChangeHealthHumanIndividualLeadLongitudinal StudiesMalignant - descriptorMalignant NeoplasmsMass Spectrum AnalysisMessenger RNAMicroRNAsMitoticModelingOncogenicOrganOutcomeOutcome StudyOxidative StressPLK1 genePaintPathway AnalysisPathway interactionsPhenotypePlayPost-Transcriptional RegulationProcessProductionProtein IsoformsProteinsProteomeProteomicsRNA SplicingRegulationResearchReverse Transcriptase Polymerase Chain ReactionRoleSamplingShapesSignal TransductionSkinSkin CancerSkin CarcinogenesisSquamous cell carcinomaSystemTestingTimeTranscriptarsenic-induced carcinogenesisbasebiological adaptation to stresscarcinogenesiscontaminated drinking waterdifferential expressiongenome-widekeratinocyteprogramsproteomic signaturepublic health relevanceresponsesodium arsenitetoxicanttranscription factortranscriptometranscriptome sequencingtranscriptomicstumorigenesiswell water
项目摘要
Project Summary
Chronic exposure to arsenic, most commonly through contaminated drinking water, plagues over 200 million
individuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenic
exposure causes several chronic diseases including cancer in multiple organs, skin cancer being the most
common. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis, a
clear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes the
transcriptomic and proteomic signatures, but the underlying mechanism for such sweeping global changes
are not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be at
play in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis in
a well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodium
arsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during the
transformation process. Our data indicate >600 differential alternative splicing events occurred at each of the
time points studied (7, 19, 28 weeks of exposure). This differential splicing program, by dramatically changing
the proteome, could be a key player in the arsenic-induced transformation of skin cells. The present proposal
aims to examine the contribution of significant differential splicing events at each time point towards the
process of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by our
transcriptomic studies can be correlated with protein isoform expression profiles. Furthermore, we also aim to
study if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts can
be correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. The
outcomes from this study will further our understanding of how alternative splicing shapes the cellular events
taking place before, during and after the time the HaCaT cells become malignant. In addition, our study will
look to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factor
can cause genome-wide synchronized alternative splicing changes by signal amplification through successive
steps, leading to altered proteome and ultimately adverse health effects.
项目摘要
长期接触砷,最常见的是通过受污染的饮用水,困扰着超过2亿人
包括美国在内的70多个国家和地区的个人。砷是一种多器官毒物,慢性砷
暴露会导致几种慢性病,包括多器官癌症,其中皮肤癌是最常见的
很普通。虽然有几种机制被认为是导致砷致癌的原因,但一个
清晰的图景尚未浮出水面。众所周知,长期接触砷会从根本上改变
转录和蛋白质组特征,但这种全面全球变化的潜在机制
目前还不清楚。差异选择性剪接在癌症发生中起作用,可能在
在砷诱导的致癌过程中发挥作用。我们使用了最先进的RNA-Seq分析
一种成熟的砷诱发皮肤癌模型(HaCaT细胞持续暴露于100 NM钠
32周)进行了一项纵向研究,以了解在
转型过程。我们的数据表明,>;600不同的选择性剪接事件发生在每个
研究时间点(暴露7、19、28周)。这种差异拼接程序,通过戏剧性地改变
该蛋白质组可能在砷诱导的皮肤细胞转化过程中发挥关键作用。目前的建议
目的是研究每个时间点的显著差异剪接事件对
致癌过程。我们将特别仔细审查我们预测的重大剪接事件
转录学研究可以与蛋白质异构体表达谱相关联。此外,我们还致力于
如果预测在转录本的5‘或3’非编码区发生显著不同的剪接异构体,研究可以
与暴露和未暴露细胞的成熟mRNA样本中的表达谱相关。这个
这项研究的结果将进一步加深我们对不同剪接如何塑造细胞事件的理解
发生在HaCaT细胞恶变之前、期间和之后。此外,我们的研究将
希望详细阐述一个上游调控替代剪接因子如何变化的机制基础
可以通过连续的信号放大引起全基因组同步的选择性剪接变化
步骤,导致蛋白质组改变,最终对健康造成不利影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('J CHRISTOPHER STATES', 18)}}的其他基金
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
10560120 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
10386901 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
10600111 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
9917940 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
10217134 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
University of Louisville Center for Integrative Environmental Health Sciences
路易斯维尔大学综合环境健康科学中心
- 批准号:
10817400 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
Alternative splicing in arsenical skin carcinogenesis
砷皮肤癌发生中的选择性剪接
- 批准号:
10215536 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
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