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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.

摘要