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.

项目总结/摘要 自身免疫性疾病无法治愈，影响了2300多万美国人。产生IL-17的T细胞 辅助细胞（Th 17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 Th 17分化和功能的机制将为治疗提供新的机会。环状rna CircRNA在细胞的各种活动中具有巨大的潜力， 不同类型的细胞。然而，CircRNA在Th 17细胞中的作用知之甚少。在本文中，circRNA 发现由Usp 3的前体mRNA（circUsp 3）产生的蛋白质对于Th 17细胞功能是必需的。我们 长期目标是开发治疗上有用的Th 17抑制剂，用于临床治疗人类 自身免疫性疾病我们在本申请中的总体目标是阐明分子机制， which哪一个circUsp 3 provides触发the Th 17 functions功能.核心假设是circUsp 3提高了Th 17分化 在体内通过与RORγt形成复合物促进Th 17介导的自身免疫。的理由 对于这个项目来说，确定circUsp 3在Th 17功能中的重要作用可能会提供证据- 这一概念表明，circRNA可以靶向治疗自身免疫性疾病。核心假设 将通过追求两个具体目标进行测试：1）确定Th 17中circUsp 3-RORγt复合物的需求 2）确定circUsp 3激活RORγ t介导的转录的机制。后 结论：CircUsp 3在Th 17功能中的作用。这些结果预计将有一个 重要的积极影响，因为它们将提供强有力的证据基础，说明以前的 Th 17功能的未被识别的基于circRNA的调节机制，最终为Th 17功能提供了机会。 开发治疗自身免疫性疾病的新疗法。这项研究具有创新性，因为 我们研究了环状RNA在Th 17功能中的作用，这是一个迄今为止尚未研究的过程。由于circRNA 在免疫细胞中广泛表达，这项研究将为探索免疫调节机制开辟一个新时代。 免疫反应。