Combating chronic neuroinflammatory disorders by targeting NAC1

项目摘要 新的调节靶点及其调节剂的发现将导致创新的策略，以提高免疫应答。 目前治疗神经炎性疾病如多发性硬化症（MS）方案的有效性， 迫切需要。最近的研究强烈表明，核小体相关蛋白-1（NAC 1）可能具有 在代谢重编程中扮演重要角色。NAC 1是BTB/POZ（广义）的转录共调节因子 复合物、tramtrack、bric-a-brac/痘病毒和锌指）基因家族，并且在各种免疫组织中高度表达。 细胞，包括T细胞。包括这个研究小组在内的已发表的研究表明，NAC 1不仅赋予了 疾病的潜力，但也破坏了治疗的结果，通过其转录依赖或- 独立的功能。最近，这个研究小组揭示了NAC 1可以通过以下方式促进糖酵解： 与HIF-1a相互作用并调节转录因子FoxP 3，而NAC 1缺陷导致小鼠 对慢性炎症和自身免疫性疾病诱导的抗性。基于这些有趣的 研究发现，该研究小组假设NAC 1在调节性T细胞（Tcells）的调节中起着关键作用。 调节免疫系统，保持对自身抗原的耐受性，预防慢性炎症， 自身免疫性疾病，并且靶向NAC 1可以用作加强基于Treg的新策略 神经炎性疾病的免疫疗法。为了测试该假设，本申请提出了 以下两个具体目标：（1）确定NAC 1在调节T细胞中的机制;以及（2）评估 靶向NAC 1在基于Treg的神经炎性疾病免疫治疗中的影响。研究团队已经 已经获得了NAC 1缺陷（NAC 1-/-）和条件性敲除（NAC 1cKO）小鼠，开发了过继细胞 本发明涉及用于所提出的研究的T细胞转移（ACT）和神经炎性疾病的鼠模型，并且是良好的。 准备实现上述目标。在第一个目标下，体外和体内方法， 在申请人的实验室中可行的，将被使用。NAC 1在调节甲状腺激素中的关键作用 将被定义。在第二个目标下，在MS的鼠模型中使用其中NAC 1缺失的TcB的ACT，即， 实验性变态反应性脑脊髓炎（EAE）是脑炎症最常见的动物模型， 将确定靶向NAC 1在基于Treg的免疫疗法中对神经炎性疾病的影响。 此外，炎症是否可以通过上调NAC 1以抑制FoxP 3来改变Treg稳定性， 表达也将被识别。这种方法是创新的，因为在癌症中靶向NAC 1的概念 神经炎性疾病以前没有被研究过。这项研究意义重大，因为 确定NAC 1在控制TcR中的作用和机制， 发展的神经炎症性疾病，并阐明了新的光NAC 1的重要性，在调节 与神经炎性疾病有关预期的临床影响将是使用NAC 1靶向 治疗策略，以显着改善ACT方案的患者与神经炎性疾病。

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.