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Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity

Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity
RNA结合蛋白和T细胞在口腔上皮可塑性中的交叉点
批准号:
10178000
负责人:
Shikhar Mehrotra
金额:
$45.49万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-01 至 2025-06-30
关键词:
BindingBiologicalBiologyCD8-Positive T-LymphocytesCell CompartmentationCell SurvivalCollaborationsCuesDataDevelopmentDiseaseDown-RegulationElementsEmbryoEnergy MetabolismEpithelialEpithelial CellsEquilibriumEukaryotaExhibitsGene ExpressionGene Expression ProfileGene Expression RegulationGenesGlycolysisHead and Neck Squamous Cell CarcinomaHealthHomeostasisHuR proteinHumanHyperplasiaIL2RA geneImmuneImmune responseImmunosuppressionInflammationInterferon Type IIIntervention StudiesKeratinKnock-outKnockout MiceLaboratoriesLeadLesionMammalian CellMass Spectrum AnalysisMediatingMessenger RNAMetabolicModelingMolecularMouth NeoplasmsMusNitroquinolinesOralOutcomeOxidative PhosphorylationOxidesPathologicPharmaceutical PreparationsPharmacologyPlayPositioning AttributePost-Transcriptional RegulationPropertyProteinsProteomicsPublishingPyrvinium pamoateRNARNA-Binding ProteinsRegulator GenesRegulatory T-LymphocyteResistanceRoleSpleenSquamous cell carcinomaT cell responseT-LymphocyteTNF geneTestingTherapeuticTherapeutic InterventionTissuesTransgenic OrganismsTranslationsTumor TissueTumor-infiltrating immune cellsVisionanti-tumor immune responsebench to bedsidecarcinogenesiscell mediated immune responsecytokineeffector T cellexperimental studyglucose metabolisminsightmalignant mouth neoplasmmouse modelmouth squamous cell carcinomaneoplastic cellnoveloral cavity epitheliumoral tumorigenesisoverexpressionpreventresponsesmall moleculetranscriptome sequencingtranscriptomicstumortumor growthtumor immunologytumor metabolismtumor microenvironmenttumor progressiontumorigenesis

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中文摘要
翻译
摘要 RNA结合蛋白(RBPs)是真核生物基因表达的重要调控因子。然而, 限制性商业惯例在口腔上皮细胞动态平衡和口腔病理疾病中的作用 大部分是难以捉摸的。我们最近的研究表明,调节失调的RBP HUR(Hu-antigen R) 破坏口腔上皮,促进口腔肿瘤的发生。HUR可以绑定富含AU的元素 并调节其翻译的稳定性。我们的初步数据显示, HUR结合并控制编码蛋白的mRNAs子集的表达 葡萄糖代谢。在与Mehrotra研究小组的合作中,我们展示了上皮特异性HUR 与免疫反应的串扰,促进口腔肿瘤的发生。利用T细胞免疫 可塑性功能,我们计划研究Hur在口腔上皮细胞和T细胞中的功能特性 用于抗肿瘤活性。在这里,我们证明了上皮细胞特异性的HUR基因敲除调控 上皮动态平衡与口腔肿瘤发生,而Hur KO T细胞增强 通过调节葡萄糖代谢来调节干扰素γ的分泌,从而改变 免疫抑制调节性T细胞(Treg‘s)和效应T细胞。而口腔上皮细胞 HUR的变化可能反映了T细胞的代谢信号,这是一个主要的悬而未决的问题 与人类口腔癌中存在免疫抑制的HUR的机制有关 和新陈代谢重新编程。总的来说,HUR针对口服中的葡萄糖代谢基因 上皮及其参与T细胞特异性免疫可塑性刺激细胞融合 Palanisamy和Mehrotra小组为阐明Hur的潜在机制所做的努力 和口腔肿瘤的发生,以及T细胞介导的免疫可塑性。最重要的是 假说认为,HUR-介导口腔上皮细胞和口腔上皮细胞之间的基因调节和串扰 一种新的免疫T细胞亚群机制及沉默HUR相关基因 网络对于上皮细胞和代谢重新编程以限制口腔癌进展至关重要。这个 我们的研究结果将导致先进的治疗干预研究和翻译 从长凳到床边。
英文摘要
ABSTRACT RNA-binding proteins (RBPs) are critical regulators of gene expression in eukaryotes. However, the contribution of RBPs in oral epithelial homeostasis and oral pathological diseases remain mostly elusive. Our recent efforts demonstrate that dysregulated RBP HuR (Hu-Antigen R) disintegrate oral epithelium and contribute to oral tumorigenesis. HuR can bind AU-rich elements of mRNA sequences and regulates its stability of translation. Our preliminary data revealed that HuR binds and controls the expression of a subset of mRNAs encoding proteins involved in glucose metabolism. In collaboration with the Mehrotra group we show that epithelial specific HuR cross talk with immune response and contribute to oral tumorigenesis. Using T-cell immune plasticity functions, we plan to study the functional properties of HuR in oral epithelial and T-cells for anti-tumor activity. Here, we demonstrated that epithelial-specific HuR knockout modulates the epithelial homeostasis and oral tumorigenesis, whereas HuR KO T cells exhibit enhanced IFNγ secretion by regulating glucose metabolism that alters the balance between the immunosuppressive regulatory T cells (Treg's) and effector T cells. While the oral epithelial alterations by HuR likely reflects the metabolic cues from T-cells, a major unanswered question pertains to the mechanism of HuR in human oral cancer where there are immune suppression and metabolic reprogramming. Collectively, HuR targets glucose metabolism genes in the oral epithelium and its involvement in T-cell specific immune plasticity stimulated a coalescence of efforts from the Palanisamy and Mehrotra groups to elucidate the underlying mechanisms of HuR and oral tumorigenesis, and T-cell mediated immune plasticity, respectively. The overarching hypothesis is that HuR-mediates gene regulation and cross-talk between oral epithelial and immune T cells compartments by a novel mechanism, and silencing HuR associated gene network is critical for epithelial and metabolic reprogramming to limit oral cancer progression. The outcome of our studies will result in advanced therapeutic intervention studies and translation from bench to bedside.
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Increasing Thiols for Improving T cell Immunotherapy
  • 批准号:
    10603006
  • 项目类别:
  • 资助金额:
    $39.42万
  • 财政年份:
    2022
  • 负责人:
    Shikhar Mehrotra
  • 依托单位:
Understanding Metabolic and Epigenetic Cross‐ talk in Potent Anti‐ tumor T cells
Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity
Programming Metabolically Fit TILs for Immunotherapy
  • 批准号:
    9906726
  • 项目类别:
  • 资助金额:
    $22.46万
  • 财政年份:
    2020
  • 负责人:
    Shikhar Mehrotra
  • 依托单位:
海外基金