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：
9107618
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：
2015-07-17 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107618
关键词：
Adoptive Transfer Affect Agonist Animals Autoimmune Diseases Autoimmune Responses Autoimmunity Binding Biology Cells Cellular biology Chromatin Circadian Rhythms Complement Complex DNA Data Development Disease Disease Progression Equilibrium Event Gene Expression Gene Targeting Generations Genetic Genetic Transcription Genetic study Goals In Vitro Individual Interleukin-17 Knock-out Ligands Maintenance Maps Mediating Mediator of activation protein Metabolism Molecular Multiple Sclerosis Nuclear Receptors Pathology Pathway interactions Physiological Processes Play Process Proteins Psoriasis Publishing Regulation Response Elements Rheumatoid Arthritis Role System Testing Therapeutic Time Tissues Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Regulation base differential expression genetic approach in vivo member mouse model new therapeutic target novel novel strategies novel therapeutics overexpression promoter public health relevance research study therapeutic development therapeutic target transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): TH17 cells have been demonstrated to play a significant role in the pathology of several autoimmune diseases. Elegant genetic studies have established that TH17 cell development and function require both the nuclear receptors (NRs) RORα and RORγt. Nevertheless, the mechanisms underlying the generation and maintenance of TH17 cells are still poorly understood, thus making the development of therapeutics targeting TH17 cells challenging. While accumulating evidence suggests complex transcriptional networks dictate TH17 cell development, a more comprehensive understanding is needed to better understand TH17 cell biology and identify novel therapeutic targets for the treatment of TH17-mediated autoimmune diseases. The REV-ERBs (REV-ERBα and REV-ERBß), 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 and genetic deletion of REV-ERBα increases IL-17A expression. In contrast, REV-ERBß deficiency decreases 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 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 unique and specific roles for each REV-ERB in the transcriptional regulation of TH17 cell development in vitro; 2) Demonstrate that the REV-ERBs are critical regulators of TH17 cell development and autoimmune disease progression in vivo; 3) Establish whether select pharmacological modulation of REV-ERB activity affects TH17 cell development and disease course in mouse models of multiple sclerosis. Successful completion of these studies will uncover a critical role for the REV-ERBs in TH17 cell biology and reveal the REV-ERBs as novel targets for the development of therapeutics to treat TH17-mediated autoimmune diseases.

描述（由申请人提供）：TH17 细胞已被证明在多种自身免疫性疾病的病理学中发挥重要作用。优雅的遗传学研究已确定 TH17 细胞的发育和功能需要核受体 (NR) RORα 和 RORγt。 TH17 细胞生成和维持的机制仍然知之甚少，因此，针对 TH17 细胞的治疗方法的开发具有挑战性，同时越来越多的证据表明复杂的转录网络决定了这一点。 TH17 细胞的发育，需要更全面的了解，以更好地了解 TH17 细胞生物学并确定治疗 TH17 介导的自身免疫性疾病的新治疗靶点 REV-ERB（REV-ERBα 和 REV-ERBß），这是该细胞的另外两个成员。 NR超家族通常与ROR在相同的组织中共表达，并结合相同的DNA反应元件，这表明它们的靶基因相互串扰和共同调节。 REV-ERB 调节许多生理过程，并以其在昼夜节律和代谢过程中的作用而闻名，虽然人们对 ROR 调节 TH17 细胞发育和功能的作用了解很多，但 REV-ERB 在这方面的生物学作用。我们的初步研究表明 REV-ERB 在调节 TH17 细胞发育中具有独特的作用，REV-ERB 的过度表达会抑制 TH17 细胞发育和基因缺失。 REV-ERBα 的缺失会增加 IL-17A 的表达，相反，REV-ERBß 的缺乏会降低 IL-17A 的表达。使用我们开发的新型 REV-ERB 特异性合成配体，我们证明 REV-ERB 活性的药理学调节会抑制 TH17 细胞。根据我们的数据，我们发现 REV-ERBS 是 TH17 细胞发育和功能的关键调节因子。 REV-ERB 特异性合成配体可能为治疗 TH17 介导的自身免疫性疾病提供新的疗法。为了检验我们的假设，我们建议 1) 确定每个 REV-ERB 在 TH17 细胞发育的转录调节中的独特和特定作用。体外；2) 证明 REV-ERB 是体内 TH17 细胞发育和自身免疫性疾病进展的关键调节因子；3) 确定 REV-ERB 是否有选择的药理调节作用这些研究的成功完成将揭示 REV-ERB 在 TH17 细胞生物学中的关键作用，并揭示 REV-ERB 作为开发治疗方法的新靶标。 TH17 介导的自身免疫性疾病。