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.

项目概要新型调节靶点及其调节剂的发现将导致增强目前的治疗方案对于多发性硬化症 (MS) 等神经炎症性疾病的有效性尚在研究中最近的研究强烈表明伏隔核相关蛋白 1 (NAC1) 可能具有迫切的需要。 NAC1 在代谢重编程中发挥着重要作用，是 BTB/POZ（广义）的转录共调节因子。复杂、tramtrack、bric-a-brac/poxvirus 和锌指）基因家族，并且在各种免疫中高度表达包括 T 细胞在内的已发表的研究表明，NAC1 不仅赋予细胞功能。疾病潜力，但也通过其转录依赖性或 - 最近，该研究小组发现NAC1可以通过促进糖酵解。与 HIF-1a 相互作用并调节转录因子 FoxP3，而 NAC1 缺乏会导致小鼠基于这些有趣的因素，可以抵抗慢性炎症和自身免疫性疾病的诱导。研究结果表明，NAC1 在调节性 T 细胞 (Treg) 的调节中发挥着关键作用调节免疫系统，维持对自身抗原的耐受性，预防慢性炎症和自身免疫性疾病，并且靶向 NAC1 可以作为增强基于 Treg 的新策略为了检验这一假设，本申请提出了针对神经炎症性疾病的免疫疗法。以下两个具体目标：（1）确定 NAC1 调节 Tregs 的机制；（2）评估研究小组研究了靶向 NAC1 对基于 Treg 的神经炎症性疾病免疫治疗的影响。已获得NAC1缺陷（NAC1-/-）和条件敲除（NAC1cKO）小鼠，开发过继细胞将 Tregs 和神经炎症性疾病的小鼠模型转移（ACT）用于拟议的研究，并且进展顺利准备通过体外和体内方法实现上述目标。在申请人的实验室中建立的可行性，将利用 NAC1 在调节 Tregs 中的关键作用。将在第二个目标下使用 Tregs 的 ACT 进行定义，其中 NAC1 在 MS 小鼠模型中被删除，即实验性过敏性脑脊髓炎（EAE）是最常见的脑部炎症动物模型在基于 Treg 的神经炎症性疾病免疫疗法中靶向 NAC1 的影响将得到确定。此外，炎症是否可以通过上调 NAC1 抑制 FoxP3 来改变 Treg 稳定性该方法也将被识别，因为靶向 NAC1 的概念。之前尚未探讨过神经炎症性疾病，因此这项研究具有重要意义。定义 NAC1 在控制 Tregs 中的作用和机制应该有助于更好地理解神经炎症性疾病的发展，并为 NAC1 在调节中的重要性提供了新的线索预期的临床影响是 NAC1 靶向药物的使用。显着改善神经炎症性疾病患者 ACT 方案的治疗策略。