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2亿多人
在包括美国在内的70多个国家。砷是一种多器官毒性物质,是慢性砷中毒
接触会导致几种慢性疾病,包括多种器官的癌症,皮肤癌是最常见的
共同虽然有几种机制被认为是负责砷诱导的致癌作用,
目前情况尚不明朗。众所周知,慢性砷暴露从根本上改变了
转录组学和蛋白质组学特征,但这种席卷全球的变化的潜在机制
还没有被清楚地理解。差异选择性剪接在肿瘤发生中起作用,
在砷诱导的致癌作用中起作用。我们采用了最先进的RNA-Seq分析,
砷诱导的皮肤癌的良好建立的模型(HaCaT细胞连续暴露于100 nM钠
亚砷酸盐32周)进行纵向研究,以了解
转化过程我们的数据表明,在每一个细胞中发生了>600个差异可变剪接事件。
研究的时间点(暴露7、19、28周)。这个差异剪接程序,通过极大地改变
蛋白质组,可能是砷诱导的皮肤细胞转化的关键角色。现时的建议
目的是检查在每个时间点显著差异剪接事件对
致癌过程。我们将特别仔细检查,如果我们预测的重大剪接事件,
转录组学研究可以与蛋白质亚型表达谱相关。此外,我们还致力于
研究是否预测在转录物的5'或3' UTR中发生的显著不同的剪接同种型可以
与来自暴露和未暴露细胞的成熟mRNA样品中的表达谱相关。的
这项研究的结果将进一步加深我们对选择性剪接如何塑造细胞事件的理解,
发生在HaCaT细胞变恶性之前、期间和之后。此外,我们的研究将
希望详细阐述一个上游调节性选择性剪接因子的变化的机制基础,
可以通过连续的信号放大引起全基因组同步的可变剪接变化,
步骤,导致改变蛋白质组,并最终对健康产生不利影响。
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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