Regulation of mRNA homeostasis by PD-L1

PD-L1 对 mRNA 稳态的调节

• 批准号: 10622760
• 负责人: Ivana Vancurova
• 金额: $ 16.4万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622760
• 关键词: Acetylation; Affect; Apoptosis; Apoptotic; Binding; Biomedical Research; Cell Surface Proteins; Cell surface; Cells; Clinical; DNA Binding; Data; Development; EP300 gene; Environment; Genes; Genetic Transcription; Goals; Homeostasis; IL8 gene; Immune; Immune response; Immunotherapy; Inflammatory; Interferon Type II; Label; Learning; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Messenger RNA; Metabolic; Nuclear Translocation; Outcome; Ovarian Stimulations; PC3 cell line; Patients; Proto-Oncogenes; RNA; RNA Polymerase II; RNA analysis; RNA-Binding Proteins; Radiation therapy; Regulation; Research; SKOV3 cells; Surface; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Thiouridine; Underrepresented Students; Universities; actinomycin; cancer cell; cancer therapy; chemokine; chromatin immunoprecipitation; cytokine; experimental study; histone acetyltransferase; immune checkpoint; immune checkpoint blockade; in vivo; mRNA Stability; mRNA Transcript Degradation; new therapeutic target; p65; programmed cell death ligand 1; promoter; prostate cancer cell; public health relevance; radiation response; recruit; response; undergraduate research experience

Abstract The goal of this project is to identify mechanisms by which immune checkpoint programmed death ligand 1 (PD-L1) regulates mRNA homeostasis of anti-apoptotic genes. As a cell surface protein, PD-L1 inhibits T cell responses, resulting in immune escape. However, PD-L1 also has important non-immune intracellular functions that are much less understood. Our recent studies show that IFNγ induces the nuclear translocation and accumulation of PD-L1 in ovarian and prostate cancer cells. In addition, our preliminary data indicate that suppression of the IFNγ-induced PD-L1 expression increases apoptosis and decreases mRNA levels of NFκB-dependent anti-apoptotic genes. Based on those findings, we will test the central hypothesis that the intracellular PD-L1 serves as a regulator of anti-apoptotic gene mRNA homeostasis. In Aim 1, we will determine whether PD-L1 increases the levels of anti-apoptotic genes by promoting their transcription, and/or whether it increases stability of their mRNAs in ovarian and prostate cancer cells. In Aim 2, we will determine whether PD-L1 directly binds to the anti-apoptotic gene promoters and facilitates their acetylation, and we will investigate whether PD-L1 binds the anti-apoptotic mRNAs and affects their subcellular localization. Although the project focuses on the NFκB-dependent anti-apoptotic genes, the results will likely reveal general mechanisms by which PD-L1 regulates synthesis and/or stability of other mRNAs. Immunotherapies targeting cell surface PD-L1 have shown impressive clinical outcomes in many cancers; however, only a fraction of patients achieves durable responses, highlighting our incomplete understanding of the mechanisms of PD-L1 functions. Findings from this study will provide the first data on the mechanisms of how PD-L1 regulates mRNA homeostasis of anti- apoptotic genes. This information will advance our understanding of the intracellular, immune- independent functions of PD-L1, and may lead to the development of novel therapies that target PD- L1 anti-apoptotic functions in cancer cells. In addition, this R16 SuRE project will enhance the research environment at St. John’s University by providing students from underrepresented backgrounds with numerous opportunities to learn the fundamentals of biomedical research.

摘要