Regulation of TH17 Cell Development and Function by the REV-ERBs

REV-ERB 对 TH17 细胞发育和功能的调节

基本信息

批准号：
9187414
负责人：
Laura A Solt
金额：
$ 48万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187414
关键词：
Adoptive Transfer Affect Agonist Attention Autoimmune Diseases Autoimmunity Binding Biology Cells Cellular biology Chromatin Circadian Rhythms DNA Data Development Disease Disease Progression Equilibrium Event Failure Gene Expression Gene Targeting Genetic Genetic Transcription Goals Homeostasis Immunity Immunologics In Vitro Individual Inflammatory Response Interleukin-17 Knock-out Ligands Maintenance Maps Mediating Metabolism Molecular Multiple Sclerosis Nuclear Receptors Pathogenesis Pathogenicity Pathology Peripheral Pharmacology Physiological Processes Play Process Proteins Psoriasis Publishing Regulation Response Elements Rheumatoid Arthritis Role Testing Therapeutic Time Tissues Transcription Coactivator Transcription Repressor/Corepressor Translating Work base cell type differential expression experimental study extracellular genetic approach in vivo knockout animal member mouse model new therapeutic target novel novel therapeutics overexpression pathogen promoter receptor response transcription factor treatment strategy

项目摘要

Project Summary / Abstract Under homeostatic conditions, TH17 cells have essential roles in protective immunity against extracellular pathogens at mucosal barriers. However, TH17 cells have also been associated with the pathogenesis of several autoimmune diseases, suggesting that failure of TH17 cell homeostasis may give rise to disease states. A significant amount of work has identified key factors that drive TH17 cell development and pathogenicity, including both the nuclear receptors (NRs) RORα and RORγt. However, cell-intrinsic mechanisms that negatively regulate TH17 cell development and associated inflammatory responses have received less attention. Therefore, a more comprehensive understanding of this cell type is needed to better understand TH17 cell biology and autoimmunity in order to identify novel therapeutic targets to treat TH17-mediated diseases. The REV-ERBs (REV-ERBα and REV-ERBβ), two other members of the NR superfamily, are often co-expressed in the same tissues as the RORs and bind the same DNA response elements, which suggest mutual cross talk and co-regulation of their target genes. The REV-ERBs regulate a number of physiological processes and are best known for their roles in the circadian rhythm and metabolic processes. While much is known about the roles for ROR regulation of TH17 cell development and function, the biology of the REV-ERBs in this process is completely unexplored. Our preliminary studies indicate that the REV-ERBs have distinct roles in the regulation of TH17 cell development. Overexpression of the REV-ERBs inhibits TH17 cell development, whereas genetic deletion of each receptor results in increased RORα/γt and CD4+IL-17A expression. Using novel REV-ERB-specific synthetic ligands that we have developed, we demonstrate that pharmacological modulation of REV-ERB activity inhibits TH17 cell development and function both in vitro and in vivo. Based on our data, we hypothesize that the REV-ERBS are key negative regulators of TH17 cell development and function and REV-ERB-specific synthetic ligands may provide novel therapeutics for the treatment of TH17-mediated autoimmune diseases. To test our hypothesis we propose to 1) Identify the roles for the REV-ERB in the regulation of TH17 cell development and function; 2) Demonstrate that the REV-ERBs are negative regulators of TH17 cell development and autoimmune disease progression in vivo; 3) Determine how REV-ERB-specific pharmacological modulation affects REV-ERB activity, TH17 cell functional responses, and autoimmunity. Successful completion of these studies will uncover key roles for the REV-ERBs in TH17 cell biology and reveal that REV-ERB-specific ligands may be a novel therapeutic strategy for the treatment of TH17-mediated autoimmune diseases.

项目概要/摘要在稳态条件下，TH17 细胞在针对细胞外物质的保护性免疫中发挥重要作用然而，TH17 细胞也与粘膜屏障的发病机制有关。多种自身免疫性疾病，表明 TH17 细胞稳态的失败可能会导致疾病状态。大量工作已经确定了驱动 TH17 细胞发育和致病性的关键因素，包括核受体 (NR) RORα 和 RORγt 然而，细胞内在机制负向调节 TH17 细胞发育和相关炎症反应受到的影响较少因此，需要对这种细胞类型有更全面的了解，才能更好地理解。 TH17 细胞生物学和自身免疫，以确定治疗 TH17 介导的新治疗靶点 REV-ERB（REV-ERBα 和 REV-ERBβ）是 NR 超家族的另外两个成员，通常与疾病有关。与 ROR 在相同的组织中共表达并结合相同的 DNA 响应元件，这表明 REV-ERB 的靶基因相互串扰和共同调节，调节许多生理学。过程，并以其在昼夜节律和代谢过程中的作用而闻名。了解 ROR 对 TH17 细胞发育和功能的调节作用、REV-ERB 的生物学我们的初步研究表明，REV-ERB 具有独特的作用。 REV-ERB 的过度表达会抑制 TH17 细胞的发育。发育，而每个受体的基因缺失会导致 RORα/γt 和 CD4+IL-17A 增加使用我们开发的新型 REV-ERB 特异性合成配体，我们证明了这一点。 REV-ERB 活性的药理调节可抑制 TH17 细胞的体外和体外发育和功能根据我们的数据，我们发现 REV-ERBS 是 TH17 细胞的关键负调节因子。发育和功能以及 REV-ERB 特异性合成配体可能为 TH17 介导的自身免疫性疾病的治疗为了检验我们的假设，我们建议 1) 确定其作用。 REV-ERB 对 TH17 细胞发育和功能的调节；2) 证明 REV-ERB 是 TH17 细胞发育和体内自身免疫性疾病进展的负调节因子； REV-ERB 特异性药理调节如何影响 REV-ERB 活性、TH17 细胞功能反应、成功完成这些研究将揭示 REV-ERB 在 TH17 中的关键作用。细胞生物学并揭示 REV-ERB 特异性配体可能是治疗 TH17 介导的自身免疫性疾病。