Determining the mechanisms by which a circular RNA regulates the function of Th17 cells

确定环状 RNA 调节 Th17 细胞功能的机制

• 批准号: 10509244
• 负责人: Zhiheng He
• 金额: $ 23.67万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-12 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509244
• 关键词: Address; Affect; American; Animal Model; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding; Biological Assay; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cell physiology; Cells; Clinical Treatment; Co-Immunoprecipitations; Code; Complement; Complex; Cytokine Signaling; Development; Exons; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Human; Hyperactivity; Immune; Immune response; Immunoprecipitation; In Vitro; Incidence; Interleukin-17; Interruption; Knock-out; Knockout Mice; Knowledge; Lead; Leukocytes; Lymphocyte; Mediating; Messenger RNA; Mission; Molecular; Mus; Names; Outcome; Phenotype; Play; Post-Translational Protein Processing; Process; Proteins; Public Health; RNA; Regulation; Research; Resistance; Role; Testing; Therapeutic; Tissues; Transactivation; Transcript; Translating; United States National Institutes of Health; Validation; autoimmune pathogenesis; base; body system; cell type; chromatin immunoprecipitation; circular RNA; conditional knockout; disability; evidence base; experimental study; gene network; in vivo; inhibitor; innovation; insight; interest; knock-down; knockout gene; mRNA Precursor; mouse model; mutant; novel therapeutics; recruit; transcription factor

PROJECT SUMMARY/ABSTRACT There is no cure for autoimmune diseases, which affect more than 23 million Americans. IL-17-producing T helper cells (Th17 cells) play a major role in the pathogenesis of autoimmune diseases. Investigating regulatory mechanisms for Th17 differentiation and function will provide new opportunities for therapeutics. Circular RNAs (circRNAs), whose functions are previously underestimated, have great potential in various cellular activities from different types of cells. However, the role of circRNAs in Th17 cells is poorly understood. Herein, a circRNA produced from the precursor mRNA for Usp3 (circUsp3) was found to be essential for Th17 cell function. Our long-term goal is to develop therapeutically useful Th17 inhibitors for the clinical treatment of human autoimmune diseases. Our overall objectives in this application are to elucidate the molecular mechanisms by which circUsp3 provokes Th17 functions. The central hypothesis is that circUsp3 elevates Th17 differentiation in vitro and promotes Th17-mediated autoimmunity in vivo through forming complex with RORγt. The rationale for this project is that determination of the essential roles of circUsp3 in Th17 function is likely to provide proof- of-concept that circRNA can be targeted to therapeutically treat autoimmune diseases. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the requirement of circUsp3-RORγt complex in Th17 function; and 2) Determine the mechanisms by which circUsp3 activates RORγt-mediated transcription. Upon conclusion, we will understand the role for circUsp3 in Th17 function. These results are expected to have an important positive impact because they will provide a strong evidence base of critical roles of previously unrecognized circRNA-based regulatory mechanisms for Th17 function, ultimately providing opportunities for the development of novel therapies to treat autoimmune diseases. The proposed research is innovative because we investigate the effect of a circular RNA in Th17 function, a heretofore-unexamined process. Since circRNAs are broadly expressed in immune cells, this study will open a new era for exploring regulatory mechanisms of immune responses.

项目概要/摘要 自身免疫性疾病无法治愈，该疾病影响着超过 2300 万美国人。产生IL-17的T 辅助细胞（Th17 细胞）在自身免疫性疾病的发病机制中发挥着重要作用。调查监管 Th17分化和功能的机制将为治疗提供新的机会。环状RNA circRNA（circRNA）的功能以前被低估，但在各种细胞活动中具有巨大潜力 来自不同类型的细胞。然而，人们对 circRNA 在 Th17 细胞中的作用知之甚少。在此，环状RNA 发现由 Usp3 (circUsp3) 前体 mRNA 产生的 Th17 细胞功能至关重要。我们的 长期目标是开发治疗上有用的 Th17 抑制剂，用于人类临床治疗 自身免疫性疾病。我们在此应用中的总体目标是通过以下方式阐明分子机制： 其中 circUsp3 会激发 Th17 功能。中心假设是 circUsp3 提升 Th17 分化 在体外，通过与 RORγt 形成复合物，在体内促进 Th17 介导的自身免疫。理由 对于这个项目来说，确定 circUsp3 在 Th17 功能中的重要作用可能会提供证据- circRNA 可用于治疗自身免疫性疾病的概念。中心假设 将通过追求两个具体目标进行测试：1) 确定 Th17 中 circUsp3-RORγt 复合物的需求 功能; 2) 确定 circUsp3 激活 RORγt 介导的转录的机制。之上 结论，我们将了解 circUsp3 在 Th17 功能中的作用。这些结果预计将有 重要的积极影响，因为它们将为以前的关键作用提供强有力的证据基础 未识别的基于 circRNA 的 Th17 功能调节机制，最终为 开发治疗自身免疫性疾病的新疗法。拟议的研究具有创新性，因为 我们研究了环状 RNA 对 Th17 功能的影响，这是一个迄今为止未经检验的过程。由于 circRNA 广泛表达于免疫细胞中，这项研究将为探索其调控机制开辟新纪元 免疫反应。