CD28 Regulation of Alternative Splicing Changes in Human T cells
CD28 对人类 T 细胞选择性剪接变化的调节
基本信息
- 批准号:10543406
- 负责人:
- 金额:$ 1.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:Alternative SplicingAntibodiesAntigen PresentationAntigen-Presenting CellsApoptoticCASP9 geneCD28 geneCD3 AntigensCD4 Positive T LymphocytesCell DeathCell SurvivalCell physiologyCellsComputer softwareCultured CellsDataEventExclusionExhibitsExonsFutureGene ExpressionGenesGeneticGoalsHarvestHigh-Throughput Nucleotide SequencingHumanImmune systemInfectionKnowledgeMessenger RNAMonoclonal Antibody HuM291PTPRC genePeptidesPhenotypePhysiologicalProcessProductionProliferatingProtein IsoformsProtein Tyrosine PhosphataseProteinsRNARNA ProcessingRNA SplicingRNA-Binding ProteinsRegulationReverse Transcriptase Polymerase Chain ReactionRoleSamplingSignal InductionSignal PathwaySignal TransductionSpliced GenesStimulusT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTitrationsTranscriptWorkcytokineexon skippingnovelpathogenreceptorresponsetooltranscriptome sequencing
项目摘要
Project Summary
Alternative splicing consists of exons that are selectively included or excluded from the mature mRNA
transcript. In fact, most protein encoding genes, approximately 95%, contain an alternative exon. Previous
studies recognized that a subset of alternative spliced genes, 10-15%, undergo changes in isoform abundance
upon activation of primary human CD4+ T cells. A well-characterized example of signal-induced alternative
splicing changes includes a tyrosine phosphatase receptor, CD45, where the increased abundance of the
shorter RNA isoform is correlated with an increased activation threshold from future stimuli. Regulatory
mechanisms including the role of signaling pathways and RNA binding proteins influencing splicing changes
have been characterized by our lab and others. However, the field lacks general knowledge of the role and
mechanism of differential T cell stimuli to regulate global splicing changes.
Previous studies investigated signal-induced alternative splicing changes with T cells activated in the
presence of anti-CD3 and anti-CD28 stimuli. CD3 is a component of the T cell receptor (TCR), which is
responsible for recognizing peptides presented by antigen presenting cells in the context of an infection. CD28
is a costimulatory receptor that enhances many signaling events downstream of the TCR. We ask if global
alternative splicing changes are differentially influenced by the presence of CD28 costimulation in primary
human CD4+ T cells. Therefore, I acquired primary CD4+ CD45RO- T cells from three human donors and
cultured the cells in the following conditions: media alone, anti-CD28 antibody, anti-CD3 antibody, or anti-
CD3/CD28 together. I harvested RNA for high-throughput sequencing analysis and discovered a subset of
alternative splicing events that are influenced by the presence CD28 costimulation compared to splicing events
regulated by CD3 stimulation alone. One of these splicing events includes a multi-exon skipping event within
Casapse-9 transcript that has not been characterized in CD4+ T cells. We hypothesize that the multi-exon
skipping event is regulating T cell survival upon stimulation. In our proposal, we plan to elucidate mechanisms
of splicing changes regulated by CD28 costimulation and the functional consequences of such events, such as
the multi-exon skipping event in Caspase-9 and impact on T cell survival. Overall, this work will be the stepping
stone into knowing how global alternative splicing events are regulated and the impact on cellular functions.
项目摘要
选择性剪接包括选择性地包含或排除在成熟mRNA之外的外显子
成绩单。事实上,大多数蛋白质编码基因,约95%,包含一个选择性外显子。先前
研究发现,10- 15%的选择性剪接基因的子集经历异构体丰度的变化,
在原代人CD 4 + T细胞活化后。信号诱导替代的一个充分表征的例子
剪接变化包括酪氨酸磷酸酶受体CD 45,其中增加的酪氨酸磷酸酶受体CD 45的丰度,
较短的RNA同种型与来自未来刺激的增加的激活阈值相关。监管
机制包括信号通路和RNA结合蛋白的作用,影响剪接的变化
已经被我们的实验室和其他实验室鉴定过了然而,该领域缺乏对这一作用的一般了解,
差异性T细胞刺激调节整体剪接变化的机制。
以前的研究调查了信号诱导的选择性剪接变化与T细胞活化,
存在抗CD 3和抗CD 28刺激物。CD 3是T细胞受体(TCR)的一种成分,
负责识别在感染情况下由抗原呈递细胞呈递的肽。CD28
是增强TCR下游的许多信号传导事件的共刺激受体。我们问如果全球
选择性剪接的变化受到CD 28共刺激的影响,
人CD 4 + T细胞。因此,我从三个人供体获得了原代CD 4 + CD 45 RO- T细胞,
在以下条件下培养细胞:单独的培养基、抗-CD 28抗体、抗-CD 3抗体或抗-
CD 3/CD 28结合。我收集RNA进行高通量测序分析,发现了一个
与剪接事件相比,受CD 28共刺激影响的选择性剪接事件
由单独的CD 3刺激调节。这些剪接事件之一包括多外显子跳跃事件,
Casapse-9转录本尚未在CD 4 + T细胞中表征。我们假设多外显子
跳跃事件是调节刺激后T细胞的存活。在我们的提案中,我们计划阐明
受CD 28共刺激调节的剪接变化以及这些事件的功能后果,例如
Caspase-9中的多外显子跳跃事件以及对T细胞存活的影响。总的来说,这项工作将是一个步骤,
了解全球可变剪接事件是如何调节的,以及对细胞功能的影响。
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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Davia Blake其他文献
Davia Blake的其他文献
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{{ truncateString('Davia Blake', 18)}}的其他基金
CD28 Regulation of Alternative Splicing Changes in Human T cells
CD28 对人类 T 细胞选择性剪接变化的调节
- 批准号:
10252785 - 财政年份:2021
- 资助金额:
$ 1.01万 - 项目类别:
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