Combating chronic neuroinflammatory disorders by targeting NAC1

项目摘要 发现新的调节靶点和它们的调节器将引导创新的战略，以增强 当前方案对多发性硬化症(MS)等神经炎性疾病的疗效 有急事。最近的研究强烈表明，伏隔核相关蛋白-1(NAC1)可能具有 在新陈代谢重新编程中起着重要作用。NAC1是BTB/POZ(BRED)的转录共调控因子 基因家族)，在多种免疫系统中高度表达。 包括T细胞在内的细胞。已发表的研究，包括这个研究小组已经表明，NAC1不仅赋予 疾病潜在性，但也通过其转录依赖或- 独立的功能。最近，这个研究小组发现，NAC1可以通过 与HIF-1a相互作用并调节转录因子FoxP3，小鼠NAC1缺乏导致 抵抗慢性炎症和自身免疫性疾病的诱导。基于这些耐人寻味 发现，该研究小组假设NAC1在调节调节性T细胞(Treg)中起关键作用 调节免疫系统，保持对自身抗原的耐受性，并防止慢性炎症和 自身免疫性疾病，靶向NAC1可被用作加强基于Treg的新策略 神经炎症性疾病的免疫治疗。为了验证这一假设，当前的应用程序提出了 以下两个具体目标：(1)确定NAC1调节Tregs的机制；(2)评估 靶向NAC1在神经炎症性疾病Treg免疫治疗中的作用。研究小组已经 已获得NAC1缺陷(NAC1-/-)和条件性基因敲除(NAC1cKO)小鼠，开发了过继细胞 Tregs和小鼠神经炎性疾病模型的转移(ACT)用于拟议的研究，并且进展良好 准备完成上述目标。在第一个目标下，体外和体内方法，已经 在申请人的实验室中确定为可行的，将被使用。NAC1在调节Tregs中的关键作用 将会被定义。在第二个目的下，使用在MS小鼠模型中缺失NAC1的Tregs的ACT，即， 实验性变态反应性脑脊髓炎(EAE)是最常见的脑部炎症动物模型， 将确定靶向NAC1在以Treg为基础的免疫疗法治疗神经炎性疾病中的影响。 此外，炎症是否可以通过上调NAC1抑制FoxP3来改变Treg的稳定性 表达也将被识别。这种方法是创新的，因为在 神经炎性疾病以前没有被研究过。这项拟议的研究意义重大，因为 明确NAC1在控制Tregs中的作用和机制应该会更好地理解 神经炎性疾病的发展，并阐明了NAC1在调节中的重要性 与神经炎性疾病有关。预期的临床影响将是使用NAC1靶向 显著改善神经炎性疾病患者的ACT方案的治疗策略。

Project Summary Discovery of novel modulatory targets and their modulators would lead innovative strategies for enhancing the effectiveness of current regimens of for neuroinflammatory disorders such as multiple sclerosis (MS) and is in urgent need. Recent studies strongly suggest that nucleus accumbens-associated protein-1 (NAC1) may have an important role in metabolic reprogramming. NAC1 is a transcription co-regulator of the BTB/POZ (broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger) gene family, and is highly expressed in various immune cells including T cells. Published studies, including this research team have shown that NAC1 not only bestows disease potential, but also undermines therapeutic consequence through its transcription-dependent or - independent functions. Lately, this research team revealed that NAC1 could promote glycolysis through interacting with HIF-1a and regulate the transcription factor FoxP3, and NAC1 deficiency in mice results in the resistance to the induction of chronic inflammation and autoimmune disorders. Based on these intriguing findings, this research team hypothesizes that NAC1 plays a key role in the regulation of regulatory T cells (Tregs) that modulate the immune system, maintain tolerance to self-antigens, and prevent chronic inflammation and autoimmune diseases, and that targeting NAC1 could be exploited as a novel strategy for reinforcing Treg-based immunotherapy for neuroinflammatory disorders. To test this hypothesis, the current application proposes the following two specific aims: (1) To determine the mechanism of NAC1 in regulating Tregs; and (2) To evaluate the impact of targeting NAC1 in Treg-based immunotherapy of neuroinflammatory disorders. The research team has already obtained NAC1 deficient (NAC1-/-) and conditional knockout (NAC1cKO) mice, developed adoptive cell transfer (ACT) of Tregs and murine models of neuroinflammatory disorders for the proposed studies, and are well poised to accomplish the above aims. Under the 1st aim, in vitro and in vivo approaches, which have been established as feasible in the applicant’s laboratory, will be used. The critical roles of NAC1 in regulating Tregs will be defined. Under the 2nd aim, using ACT of Tregs in which NAC1 is deleted in a murine model of MS, i.e., experimental allergic encephalomyelitis (EAE), the most common animal model for brain inflammation, the impact of targeting NAC1 in Treg-based immunotherapy for neuroinflammatory disorders will be determined. Furthermore, whether inflammation can alter Treg stability through the upregulation of NAC1 to inhibit FoxP3 expression will also be identified. The approach is innovative, because the concept of targeting NAC1 in neuroinflammatory disorders has not been previously explored. The proposed research is significant, because defining the roles and mechanisms of NAC1 in controlling Tregs should yield a better understanding of the development of neuroinflammatory disorders, and shed new lights on the importance of NAC1 in the regulation related to neuroinflammatory disorders. The anticipated clinical impact would be the use of the NAC1-targeted therapeutic strategy to significantly improve the ACT regimen for patients with neuroinflammatory disorders.