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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

基本信息

批准号：
10814585
负责人：
Zhiheng He
金额：
$ 21.13万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-12 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10814585
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 Code Complement Complex Cytokine Signaling Development Exons Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Helper-Inducer T-Lymphocyte Human Hyperactivity IL17 gene Immune Immune response Immunoprecipitation In Vitro Incidence Interruption Knock-out Knockout Mice Knowledge 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 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 ubiquitin isopeptidase

项目摘要

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/文摘