Combating chronic neuroinflammatory disorders by targeting NAC1

通过靶向 NAC1 对抗慢性神经炎症性疾病

基本信息

批准号：
10631164
负责人：
Jianxun Jim Song
金额：
$ 18.73万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631164
关键词：
Adoptive Cell Transfers Affect Amyloid beta-Protein Animal Model Animals Anti-Inflammatory Agents Antibodies Antigens Antiinflammatory Effect Autoantigens Autoimmune Diseases Autoimmunity Brain Bypass Cell model Cells Cellular Immunology Cellular immunotherapy Chronic Clinical Complex Data Development Disease Dose Effectiveness Encephalitis Encephalomyelitis Experimental Autoimmune Encephalomyelitis FOXP3 gene Gene Family Generations Genetic Transcription Glycolysis Goals Hematopoietic Stem Cell Transplantation Human Immune Immune response Immune system Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Inflammation Inflammatory Interleukin-2 Knockout Mice Knowledge Laboratories Lead Mediating Metabolic Modality Multiple Sclerosis Mus Myasthenia Gravis Nucleus Accumbens Outcome Patients Play Poxviridae Production Proteins Publishing Regimen Regulation Regulatory T-Lymphocyte Research Resistance Role Signal Pathway Site Spinal Cord Suppressor-Effector T-Lymphocytes T-Lymphocyte Testing Therapeutic Tumor Necrosis Factor-Beta Up-Regulation Zinc Fingers clinical efficacy conditional knockout design epigenetic regulation first-in-human graft vs host disease immunoregulation improved in vivo innovation insight mouse model multiple sclerosis treatment neuroinflammation novel novel strategies prevent response side effect targeted treatment trafficking transcription factor

项目摘要

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.

项目摘要发现新型调制目标及其调节器将领导创新策略以增强当前治疗方案对于神经炎症性疾病（例如多发性硬化症（MS））的有效性，急需。最近的研究强烈表明，伏隔核相关蛋白-1（NAC1）可能具有在代谢重编程中的重要作用。 NAC1是BTB/POZ的转录共同调节器复合物，轨道，bric-a-a-brac/poxvirus和锌指基因家族，并在各种免疫中高度表达包括T细胞在内的细胞。包括该研究团队在内的已发表研究表明，NAC1不仅授予疾病潜力，但也通过其转录依赖性或 - 独立功能。最近，该研究小组透露NAC1可以通过与HIF-1A相互作用并调节转录因子FOXP3，而小鼠的NAC1缺乏导致抗慢性炎症和自身免疫性疾病的抗性。基于这些有趣的调查结果，该研究团队假设NAC1在调节T细胞（TREG）的调节中起关键作用调节免疫系统，保持对自我抗原的耐受性，并防止慢性感染和自身免疫性疾病，靶向NAC1可以作为增强基于Treg的新型策略探索神经炎症性疾病的免疫疗法。为了检验该假设，当前的申请提出了遵循两个具体的目的：（1）确定NAC1在调节Treg中的机制；（2）评估靶向NaC1在基于TREG的神经炎症性疾病的免疫疗法中的影响。研究小组有已经获得了NAC1缺乏（NAC1 - / - ）和有条件的敲除（NAC1CKO）小鼠，开发了自适应细胞拟议研究的神经炎性疾病的Tregs和鼠模型的转移（ACT），并且很好中毒以实现上述目标。在第一个目标下，体外和体内方法将使用在申请人的实验室中可行的。 NAC1在调节Treg中的关键作用将定义。在第二个目标下，使用Treg的行为，其中NaC1在MS的鼠模型中被删除，即实验性过敏性脑脊髓炎（EAE），最常见的脑注射动物模型，将确定靶向NaC1在基于TREG的免疫疗法中对神经炎症性疾病的影响。此外，炎症是否可以通过NAC1上调抑制Foxp3改变Treg稳定性表达也将被识别。这种方法是创新的，因为针对NAC1的概念神经炎症性疾病以前尚未探讨。拟议的研究很重要，因为定义NAC1在控制Tregs中的作用和机制应更好地理解神经炎症性疾病的发展，并为NAC1的重要性开发了新的灯光与神经炎症性疾病有关。预期的临床影响是使用NAC1靶向治疗策略可显着改善神经炎症性疾病患者的ACT方案。