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

• 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
• 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

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.

项目摘要/摘要 在动态平衡条件下，TH17细胞在细胞外免疫保护中具有重要作用 粘膜屏障上的病原体。然而，TH17细胞也与肺癌的发病机制有关。 几种自身免疫性疾病，提示TH17细胞动态平衡的失稳可能导致疾病状态。 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(NRs)RoRα和RoRγt。然而， 负向调节TH17细胞发育和相关的炎症反应收到的较少 请注意。因此，需要更全面地了解这种细胞类型，才能更好地了解 Th17细胞生物学和自身免疫，以寻找治疗Th17介导的新的治疗靶点 疾病。REV-ERB(REV-ERBα和REV-ERBβ)是NR超家族的另外两个成员，通常 在与Rors相同的组织中共表达，并结合相同的DNA反应元件，这表明 相互串扰和共同调节他们的目标基因。REV-ERB调节许多生理性的 它们在昼夜节律和新陈代谢过程中的作用而广为人知。虽然很多都是 已知ROR在TH17细胞发育和功能调节中的作用，REV-ERBS的生物学 在这个过程中是完全没有被探索过的。我们的初步研究表明，REV-ERBS具有明显的 在调节TH17细胞发育中的作用。REV-ERBS过表达抑制TH17细胞 发育，而每个受体的基因缺失导致RORCD4t和α/γ+IL-17A增加 表情。使用我们开发的新型REV-ERB特异性合成配体，我们证明了 药物调节REV-ERB活性在体外和体外抑制TH17细胞的发育和功能 在活体内。根据我们的数据，我们假设REV-ERBS是TH17细胞的关键负调控因子 发展和功能及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)确定角色 对于REV-ERB在调节TH17细胞发育和功能中的作用；2)证明REV-ERBS 是体内TH17细胞发育和自身免疫性疾病进展的负调控因素；3)确定 REV-ERB特异性药理调节如何影响REV-ERB活性，TH17细胞功能反应， 和自身免疫力。这些研究的成功完成将揭示REV-ERBS在TH17中的关键作用 细胞生物学，并揭示了REV-ERB特异性配体可能是一种新的治疗策略 Th17介导的自身免疫性疾病。