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

基本信息

批准号：
10632129
负责人：
Shikhar Mehrotra
金额：
$ 0.34万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2020-07-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10632129
关键词：
Binding Biological Biology CD8-Positive T-Lymphocytes Cell Compartmentation Cell Separation Cell Survival Collaborations Cues Data Development Disease Down-Regulation Elements Embryo Energy Metabolism Epithelial Cells Epithelium Equilibrium Eukaryota Exhibits Gene Expression Gene Expression Profile Gene Expression Regulation Genes Glycolysis Head and Neck Squamous Cell Carcinoma Health Homeostasis HuR protein Human Hyperplasia IL2RA gene Immune Immune response Immunosuppression Inflammation Inflammatory Interferon Type II Intervention Studies Keratin Knock-out Knockout Mice Laboratories Lead Lesion LoxP-flanked allele Mammalian Cell Mass Spectrum Analysis Mediating Messenger RNA Metabolic Modeling Molecular Mouth Neoplasms Mus Nitroquinolines Oral Outcome Oxidative Phosphorylation Oxides Pathologic Pharmaceutical Preparations Play Positioning Attribute Post-Transcriptional Regulation Proliferating Property Proteins Proteomics Publishing Pyrvinium pamoate RNA RNA-Binding Proteins Regulator Genes Regulatory T-Lymphocyte Resistance Role Spleen Squamous cell carcinoma T cell response T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Intervention Tissues Transgenic Organisms Translations Tumor Tissue Vision anti-tumor immune response bench-to-bedside translation carcinogenesis cell mediated immune response cytokine effector T cell experimental study gene network glucose metabolism immune cell infiltrate insight malignant mouth neoplasm mouse model mouth squamous cell carcinoma neoplastic cell novel oral cavity epithelium oral tumorigenesis overexpression pharmacologic prevent response small molecule transcriptome sequencing transcriptomics tumor tumor growth tumor immunology tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

抽象的 RNA结合蛋白（RBP）是真核生物基因表达的关键调节剂。 RBP在口腔上皮稳态和口腔病理疾病中的贡献仍然存在我们最近难以捉摸。分解口服上皮，并导致口服肿瘤发生。 mRNA序列和常规的是我们的预后数据的稳定性。 HUR结合并控制了涉及蛋白质的mRNA子集的表达葡萄糖代谢与Mehrotra集团合作与免疫反应的交叉交流，并使用T细胞免疫有助于口服肿瘤可校准功能，我们计划研究口腔上皮和T细胞中HUR的功能性能对于抗肿瘤活动。上皮稳态和口服肿瘤发生，而Hur Ko T细胞表现出增强通过调节葡萄糖代谢，IFNγ分泌免疫性调节T细胞（Treg）和效应T细胞。 HUR的改变可能反映了T细胞的代谢线索，这是一个主要的未解决的问题免疫抑制的人类口腔癌中HUR机制的持久性和代谢重编程。上皮及其参与T细胞特异性免疫可塑性刺激了合并 Palanisamy和Mehrotra群体的努力阐明了HUR的基本机制口服肿瘤发生，T细胞介导的免疫塑料假设是HUR医学基因调节和口腔上皮之间的跨标准。免疫T细胞隔室网络对于限制口腔癌的上皮和代谢重编程至关重要我们研究的结果将导致先进的治疗干预研究和翻译从长凳到床边。