Regulation of TH17 cell development and function by the REV-ERBs

DESCRIPTION（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中发挥重要作用。遗传学研究已经证实TH17细胞的发育和功能需要核受体（nr） RORα和RORγt。然而，TH17细胞产生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。虽然越来越多的证据表明，复杂的转录网络决定TH17细胞的发育，但需要更全面的理解，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-ERBs （REV-ERBα和REV-ERBß）是NR超家族的另外两个成员，它们通常与RORs在相同的组织中共表达，并结合相同的DNA应答元件，这表明它们的靶基因相互串话和共同调控。REV-ERBs调节许多生理过程，最广为人知的是它们在昼夜节律和代谢过程中的作用。虽然我们对ROR调控TH17细胞发育和功能的作用了解甚多，但REV-ERBs在这一过程中的生物学作用却完全未知。我们的初步研究表明REV-ERBs在TH17细胞发育的调控中具有不同的作用。过表达REV-ERBs抑制TH17细胞发育，基因缺失REV-ERBα增加IL-17A表达。相反，REV-ERBß缺乏会降低IL- 17A的表达。利用我们开发的新型REV-ERB特异性合成配体，我们证明了REV-ERB活性的药理学调节可以抑制TH17细胞的体外和体内发育和功能。基于我们的数据，我们假设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治疗方法。为了验证我们的假设，我们提出：1)确定每个REV-ERB在体外TH17细胞发育转录调控中的独特和特定作用；2)证明REV-ERBs是体内TH17细胞发育和自身免疫性疾病进展的关键调节因子；3)确定REV-ERB活性的选择性药理调节是否影响多发性硬化症小鼠模型中TH17细胞的发育和病程。这些研究的成功完成将揭示REV-ERBs在TH17细胞生物学中的关键作用，并揭示REV-ERBs是开发治疗TH17介导的自身免疫性疾病的新靶点。

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.