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：
10417171
负责人：
Shikhar Mehrotra
金额：
$ 45.19万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417171
关键词：
Binding Biological Biology CD8-Positive T-Lymphocytes Cell Compartmentation Cell Survival Collaborations Cues Data Development Disease Down-Regulation Elements Embryo Energy Metabolism Epithelial Epithelial Cells 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 Interferon Type II Intervention Studies Keratin Knock-out Knockout Mice Laboratories Lead Lesion Mammalian Cell Mass Spectrum Analysis Mediating Messenger RNA Metabolic Modeling Molecular Mouth Neoplasms Mus Nitroquinolines Oral Outcome Oxidative Phosphorylation Oxides Pathologic Pharmaceutical Preparations Pharmacology Play Positioning Attribute Post-Transcriptional Regulation 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 Tumor-infiltrating immune cells Vision anti-tumor immune response bench-to-bedside translation carcinogenesis cell mediated immune response cytokine effector T cell experimental study gene network glucose metabolism insight malignant mouth neoplasm mouse model mouth squamous cell carcinoma neoplastic cell novel oral cavity epithelium oral tumorigenesis overexpression 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。然而， RBP在口腔上皮稳态和口腔病理疾病中的贡献仍然存在主要难以捉摸。我们最近的努力表明RBP HUR（HU-ANTIGEN R）失调分解口服上皮，并导致口服肿瘤发生。 HUR可以束缚Au-Rich元素 mRNA序列并调节其翻译的稳定性。我们的初步数据表明 HUR结合并控制了涉及蛋白质的mRNA子集的表达葡萄糖代谢。在与Mehrotra集团的合作中，我们表明上皮特定的HUR 交叉与免疫反应进行交谈，并导致口腔肿瘤发生。使用T细胞免疫可塑性功能，我们计划研究口腔上皮和T细胞中HUR的功能特性用于抗肿瘤活性。在这里，我们证明了上皮特异性的HUR敲除调节上皮稳态和口腔肿瘤发生，而Hur Ko T细胞暴露了通过反思葡萄糖代谢来改变的IFNγ分泌免疫抑制性调节T细胞（Treg）和效应T细胞。而口腔上皮 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与受到免疫抑制的人类口腔癌的HUR机制有关和代谢重编程。 HUR共同靶向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了合并 Palanisamy和Mehrotra群体的努力阐明了HUR的基本机制和口腔肿瘤发生，分别是T细胞介导的免疫可塑性。总体假设是Hur-erediat在口腔上皮和免疫T细胞通过一种新型机制隔室，并使HUR相关基因沉默网络对于限制口腔癌进展的上皮和代谢重编程至关重要。这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。