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 该项目的目的是确定免疫检查站编程死亡的机制 配体1（PD-L1）调节抗凋亡基因的mRNA稳态。作为细胞表面蛋白， PD-L1抑制T细胞反应，从而导致免疫逃脱。但是，PD-L1也很重要 少理解的非免疫细胞内功能。我们最近的研究表明IFNγ 诱导PD-L1在卵巢和前列腺癌细胞中的核易位和积累。 此外，我们的初步数据表明抑制IFNγ诱导的PD-L1表达 增加凋亡并降低NFκB依赖性抗凋亡基因的mRNA水平。基于 关于这些发现，我们将测试中心假设，即细胞内PD-L1用作 抗凋亡基因mRNA稳态的调节剂。在AIM 1中，我们将确定PD-L1是否 通过促进抗凋亡基因的转录和/或是否增加了抗凋亡基因的水平 提高其在卵巢和前列腺癌细胞中mRNA的稳定性。在AIM 2中，我们将确定 PD-L1是否直接与抗凋亡基因启动子结合并促进其乙酰化， 我们将研究PD-L1是否结合抗凋亡mRNA并影响其亚细胞 尽管该项目着重于NFκB依赖性抗凋亡基因，但结果 可能会揭示PD-L1调节其他的合成和/或稳定性的一般机制 mrnas。靶向细胞表面PD-L1的免疫疗法显示出令人印象深刻的临床结果 许多癌症；但是，只有一小部分患者获得了持久的反应，突显了我们的 对PD-L1功能机制的不完全理解。这项研究的发现将 提供有关PD-L1如何调节mRNA稳态的机制的第一个数据 凋亡基因。这些信息将提高我们对细胞内免疫的理解 PD-L1的独立功能，并可能导致靶向PD-的新型疗法的发展 L1癌细胞中的抗凋亡功能。此外，此R16确定项目将增强 圣约翰大学的研究环境通过为人数不足的学生提供 有很多机会学习生物医学研究的基础知识的背景。