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.

抽象的 该项目的目标是确定免疫检查点程序性死亡的机制 配体 1 (PD-L1) 调节抗凋亡基因的 mRNA 稳态。 PD-L1 抑制 T 细胞反应，导致免疫逃逸。然而，PD-L1 也有重要作用。 我们最近的研究表明，IFNγ 具有非免疫细胞内功能。 诱导卵巢癌细胞和前列腺癌细胞中 PD-L1 的核转位和积累。 此外，我们的初步数据表明，抑制 IFNγ 诱导的 PD-L1 表达 增加细胞凋亡并降低 NFκB 依赖性抗细胞凋亡基因的 mRNA 水平。 根据这些发现，我们将检验细胞内 PD-L1 作为 在目标 1 中，我们将确定 PD-L1 是否是抗凋亡基因 mRNA 稳态的调节剂。 通过促进抗凋亡基因的转录来提高抗凋亡基因的水平，和/或是否 提高卵巢癌细胞和前列腺癌细胞中 mRNA 的稳定性。在目标 2 中，我们将确定。 PD-L1是否直接结合抗凋亡基因启动子并促进其乙酰化， 我们将研究PD-L1是否结合抗凋亡mRNA并影响其亚细胞 尽管该项目的重点是 NFκB 依赖性抗凋亡基因，但结果 可能会揭示 PD-L1 调节其他物质合成和/或稳定性的一般机制 靶向细胞表面 PD-L1 的 mRNA 免疫疗法已显示出令人印象深刻的临床效果。 许多癌症；然而，只有一小部分患者获得了持久的缓解，这凸显了我们的研究 本研究的结果将导致对 PD-L1 功能机制的不完全理解。 提供了关于 PD-L1 如何调节抗-细胞因子 mRNA 稳态的机制的第一个数据 这些信息将增进我们对细胞内免疫基因的理解。 PD-L1 的独立功能，并可能导致针对 PD-L1 的新疗法的开发 此外，R16 SuRE项目将增强L1在癌细胞中的抗凋亡功能。 圣约翰大学为来自代表性不足的学生提供研究环境 拥有大量学习生物医学研究基础知识的机会。