Understanding mechanisms and consequences of T cell co-receptor regulated RNA maturation

了解 T 细胞辅助受体调节 RNA 成熟的机制和后果

• 批准号: 10589052
• 负责人: Scott Henry Olejniczak
• 金额: $ 51.69万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589052
• 关键词: Affect; Alternative Splicing; Applications Grants; Autoimmune Diseases; Autoimmunity; CD28 gene; CD8-Positive T-Lymphocytes; Cell Proliferation; Cell physiology; Cells; Code; Communicable Diseases; Data; Degradation Pathway; Elements; Enzymes; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetically Engineered Mouse; Glucose; Glycolysis; Goals; Human; Immunotherapy; In Vitro; Introns; Investigation; Knowledge; Link; Literature; Malignant Neoplasms; Messenger RNA; Metabolic; Modeling; Modernization; Molecular Immunology; Mutation; Normal tissue morphology; Nuclear; Nuclear RNA; Nutrient; PD-1 blockade; Pathway interactions; Patients; Phase; Process; Production; Proliferating; Property; Protein Isoforms; Proteins; Pyruvate Kinase; RNA; RNA Splicing; RNA-Binding Proteins; Receptor Cross-Talk; Receptor Signaling; Regulation; Reporting; Research; Role; Shapes; Signal Transduction; Sorting; Surface; T cell regulation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Transcript; Work; cancer cell; cell type; discrete time; experimental study; functional gain; functional outcomes; in vivo; insight; mutant; neoplastic cell; novel; programmed cell death protein 1; programs; receptor; receptor function; recruit; response; synergism; targeted treatment; therapeutic target; transcriptome; tumor growth

Project Abstract/Summary. T cells are unique in their requirement for two activation signals to become functional. This separation of powers between the T cell receptor (TCR) and co-receptors, such as CD28, allows exquisite regulation of T cell responses. In recent years, T cell co-receptors have emerged as valuable targets of immunotherapy for autoimmune diseases and cancer. In autoimmunity blocking activating co-receptors can reduce the destructive effects of T cells on normal tissue, while in cancer blocking inhibitory co-receptors can activate a T cell response against malignant cells. However, co-receptor targeted immunotherapy often fails to produce desired results. Moreover, there remain large gaps in knowledge of how co-receptors coordinate the myriad cellular changes that allow T-cells to gain functional properties. The project proposed in this grant application will explore a novel mechanism by which T cell co-receptors coordinate changes in RNA maturation important for T-cells to generate sufficient numbers and make key molecules that allow them to kill other cells. These killer properties underlie the ability of T cells to contain infectious diseases and control tumor growth or to damage healthy tissue in autoimmune diseases. Preliminary studies provide evidence that CD28 signaling coordinates many changes in alternative splicing of newly made RNAs through effects on the RNA binding protein ARS2. Alternative splicing allows one gene to code for several different proteins by changing how the RNA produced from that gene is assembled. We find that in activated T cells CD28-ARS2 dependent alternative splicing of the mRNA coding for metabolic enzyme pyruvate kinase favors production of an isoform, known as PKM2, with known proliferation promoting properties. Proposed studies seek to 1) determine if alternative splicing to PKM2 induces changes in how T cells use nutrients to fuel proliferation, 2) examine how ARS2 regulates alternative splicing in T cells, and 3) establish CD28 regulated changes in alternative splicing as potential modulators of immunotherapy. The long-term goals of these studies are to understand how RNA binding proteins and RNA maturation shapes gene expression during the process of T-cell activation and to determine if such mechanisms of gene regulation can be therapeutically targeted to alter T-cell function in patients with cancer or autoimmune diseases.

项目摘要/总结。 T细胞的独特之处在于它们需要两种激活信号才能发挥功能。的这种分离 T细胞受体（TCR）和辅助受体（如CD 28）之间的相互作用，使得T细胞受体（TCR）能够精确调节， 细胞反应。近年来，T细胞共受体已经成为免疫治疗的有价值的靶标，用于治疗癌症。 自身免疫性疾病和癌症。在自身免疫中，阻断激活辅助受体可以减少免疫系统的破坏性。 T细胞对正常组织的影响，而在癌症中，阻断抑制性共受体可以激活T细胞 对恶性细胞的反应。然而，共受体靶向免疫疗法通常不能产生期望的免疫应答。 结果此外，在共受体如何协调细胞内的无数细胞因子方面， 使T细胞获得功能特性的变化。本资助申请中提出的项目将 探索T细胞辅助受体协调RNA成熟变化的新机制， T细胞产生足够的数量并产生关键分子，使它们能够杀死其他细胞。这些杀 这些特性是T细胞抑制感染性疾病和控制肿瘤生长或破坏 自身免疫性疾病中的健康组织。初步研究提供证据表明，CD 28信号协调 通过对RNA结合蛋白ARS 2的影响，新产生的RNA的选择性剪接发生了许多变化。 选择性剪接允许一个基因通过改变RNA的产生方式来编码几种不同的蛋白质 是由这个基因组成的。我们发现，在活化的T细胞中，CD 28-ARS 2依赖性的选择性剪接， 编码代谢酶丙酮酸激酶的mRNA有利于产生称为PKM 2的同种型， 已知的增殖促进特性。拟议的研究试图1）确定PKM 2的选择性剪接是否 诱导T细胞如何利用营养物质来促进增殖的变化，2）研究ARS 2如何调节替代 在T细胞中的剪接，和3）建立CD 28调节的可变剪接的变化作为潜在的调节剂， 免疫疗法。这些研究的长期目标是了解RNA结合蛋白和RNA 成熟在T细胞活化过程中塑造基因表达，并确定这种 基因调控机制可以在治疗上靶向改变癌症患者的T细胞功能， 自身免疫性疾病