New approaches to combat CNS inflammation in Veterans: Targeting a metabolic enzyme in demyelinating disease

对抗退伍军人中枢神经系统炎症的新方法：针对脱髓鞘疾病中的代谢酶

基本信息

批准号：
9565043
负责人：
BRIAN A. ZABEL
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565043
关键词：
Active Immunization Acyl Coenzyme A Acyltransferase Affect All-Trans-Retinol American Animal Model Animals Autoimmune Process Automobile Driving Blood Brain CD4 Positive T Lymphocytes Cell physiology Cells Cellular biology Clinical Clinical Trials Data Demyelinating Diseases Development Diglycerides Disease Disease Progression Enzymes Esters Experimental Autoimmune Encephalomyelitis FOXP3 gene Family Goals Health Heterogeneity Histology Human Immune Immunosuppression In Vitro Incidence Inflammation Inflammatory Injury Interferon Type II Interleukin-17 Knockout Mice Lead Lesion Leukocytes Lipid A Lipids Magnetic Resonance Imaging Medical Metabolic Metabolic Pathway Metabolism Military Personnel Molecular Multiple Sclerosis Mus Myelin Myelin Sheath Neuraxis Obesity associated disease Onset of illness Outcome Pathogenesis Pathogenicity Pathology Peptides Persons Pharmaceutical Preparations Phase Phase II Clinical Trials Play Population Process Regulatory T-Lymphocyte Relapse Research Project Grants Retinoids Risk Role Serum Spinal Cord Supplementation Symptoms T cell differentiation T cell response T-Cell Development T-Lymphocyte TNF gene Testing Therapeutic Tissues Toxic effect Triglycerides Veterans Vitamin A autoreactivity base central nervous system demyelinating disorder cohort combat cytokine diacylglycerol O-acyltransferase dietary manipulation disorder risk drug development effector T cell improved in vivo individual patient inhibitor/antagonist insight interleukin-22 multiple sclerosis patient multiple sclerosis treatment novel novel strategies novel therapeutics obesity treatment oligodendrocyte-myelin glycoprotein patient response pre-clinical prevent response safety study selective expression side effect small molecule

项目摘要

Multiple sclerosis (MS) is a debilitating demyelinating disease of the central nervous system (CNS) that affects approximately 2.5 million people worldwide. US military personnel are at special risk to develop MS: the incidence rate in the US military population (12.9 per 100,000 person-years) is 1.7x higher than the civilian population, and 3x higher than the global population. Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many features of human MS. Tissue injury in EAE and MS is caused by inflammatory leukocytes that enter the CNS and destroy myelin. CNS-infiltrating, myelin-reactive CD4+ T cells play key roles in the pathology of MS. Although a number of MS treatments are available, due to the heterogeneity of the MS disease process, individual patient responses, and medication toxicities, there is a substantial unmet clinical need for improved therapeutics. T cell differentiation and function is profoundly affected by the engagement of metabolic pathways retinoid processing. Diacylglycerol O-acyltransferase-1 (DGAT1) is a metabolic enzyme that can catalyze the synthesis of triglycerides (TG, via DGAT activity), and retinyl esters (RE, via acyl CoA:retinol acyltransferase (ARAT) activity). Little is known regarding the role of DGAT1 in T cell biology. Our preliminary studies suggest that DGAT1 is selectively upregulated in activated mouse CD4+ T cells both in vitro and in vivo during EAE. DGAT1 is selectively expressed in brain lesions and CD4+ blood T cells obtained from MS patients. DGAT1 KO mice are protected against EAE, and DGAT1 pharmaco-inhibition suppresses EAE. Based on our preliminary data and the importance of retinoid metabolism in governing T cell differentiation and function, we hypothesize that T cell-expressed DGAT1 plays a key role in regulating pathogenic T cell activity in autoimmune demyelinating disease. In Aim 1 we will investigate the translational utility of targeting DGAT1 with small molecule antagonists to treat demyelinating disease. We will test the hypothesis that human blood CD4+ T cells express DGAT1 and contain DGAT/ARAT activity, and that DGAT1 regulates Treg and Th17 differentiation and function. We will also test the hypothesis that DGAT1 inhibitors administered after disease onset will reverse EAE progression and prevent relapse. Notably, small-molecule DGAT1 inhibitors are already being tested in clinical trials for treatment of obesity-associated diseases. Thus the studies in Aim 1 may uncover new MS-specific applications for existing drugs that have already cleared Phase I safety studies. In Aim 2 we propose to define the role of DGAT1 in CD4+ effector T cell formation and function. Using in vitro polarized CD4+ T cells, we will define DGAT1 expression and ARAT activity in mouse Treg and Th17 cells. Using naive T cells from WT and DGAT1 KO mice, we will define the role of DGAT1 in Treg and Th17 differentiation and function. To facilitate the study of DGAT1 in Treg development, we propose to generate DGAT1 KO/Foxp3/GFP mice (DGAT1 KO mice with GFP+ Tregs). In Aim 3, we propose to generate T cell conditional inducible DGAT1 KO mice (CD4CreERT2 -DGAT1fl/fl) to define the role of T cell-expressed DGAT1 in EAE. Finally, in Aim 4 we will investigate how dietary manipulation of vitamin A impacts the effects of DGAT1 deficiency in EAE. The results from this aim may provide a mechanistic rationale for vitamin A supplementation in MS, as low levels of vitamin A are associated with increased disease risk, and serum retinol levels are inversely correlated with magnetic resonance imaging outcomes in MS. Together, the proposed studies promise to elucidate novel insight into T cell immunometabolism and the role of DGAT1 in driving disease pathogenesis in MS, and holds great translational potential to reduce the impact of MS on US Veterans, their families, and the American public.

多发性硬化症 (MS) 是一种使人衰弱的中枢神经系统 (CNS) 脱髓鞘疾病，影响全球约 250 万人。美国军事人员面临罹患多发性硬化症的特殊风险：美国军人的发病率（每 10 万人年 12.9 例）比平民高 1.7 倍人口，比全球人口高出 3 倍。实验性自身免疫性脑脊髓炎（EAE）是一种广泛研究的动物模型具有人类多发性硬化症的许多特征。 EAE 和 MS 中的组织损伤是由由进入中枢神经系统并破坏髓磷脂的炎症白细胞引起。 CNS 浸润、髓磷脂反应性 CD4+ T 细胞在多发性硬化症的病理学中发挥着关键作用。尽管有多种多发性硬化症治疗方法可供选择，但由于由于多发性硬化症疾病过程、患者个体反应和药物毒性的异质性，存在对改进治疗方法的大量未满足的临床需求。 T 细胞的分化和功能深受类视黄醇代谢途径的影响加工。二酰基甘油 O-酰基转移酶-1 (DGAT1) 是一种代谢酶，可以催化甘油三酯（TG，通过 DGAT 活性）和视黄酯（RE，通过酰基 CoA：视黄醇酰基转移酶）的合成（ARAT）活动）。关于 DGAT1 在 T 细胞生物学中的作用知之甚少。我们的初步研究表明在 EAE 期间，DGAT1 在体外和体内激活的小鼠 CD4+ T 细胞中选择性上调。 DGAT1 在脑损伤和从 MS 患者获得的 CD4+ 血 T 细胞中选择性表达。 DGAT1 KO 小鼠可免受 EAE 侵害，而 DGAT1 药物抑制可抑制 EAE。基于我们的初步数据和类维生素A代谢在控制T细胞分化和功能中的重要性，我们假设 T 细胞表达的 DGAT1 在调节致病性 T 细胞活性中起关键作用自身免疫性脱髓鞘疾病。在目标 1 中，我们将研究用小分子拮抗剂靶向 DGAT1 的转化效用治疗脱髓鞘疾病。我们将检验人类血液 CD4+ T 细胞表达 DGAT1 和含有 DGAT/ARAT 活性，并且 DGAT1 调节 Treg 和 Th17 分化和功能。我们将还检验了疾病发作后施用 DGAT1 抑制剂将逆转 EAE 进展的假设并防止复发。值得注意的是，小分子 DGAT1 抑制剂已经在临床试验中进行测试治疗肥胖相关疾病。因此，目标 1 中的研究可能会发现新的 MS 特异性已通过第一阶段安全性研究的现有药物的申请。在目标 2 中，我们建议定义 DGAT1 在 CD4+ 效应 T 细胞形成和功能中的作用。使用体外极化 CD4+ T 细胞，我们将定义小鼠 Treg 和 Th17 细胞中的 DGAT1 表达和 ARAT 活性。使用来自 WT 的初始 T 细胞和 DGAT1 KO 小鼠，我们将定义 DGAT1 在 Treg 和 Th17 分化和功能中的作用。为了方便为了研究 DGAT1 在 Treg 发育中的作用，我们建议生成 DGAT1 KO/Foxp3/GFP 小鼠（DGAT1 KO 具有 GFP+ Tregs 的小鼠）。在目标 3 中，我们建议生成 T 细胞条件诱导的 DGAT1 KO 小鼠 (CD4CreERT2 -DGAT1fl/fl) 定义 T 细胞表达的 DGAT1 在 EAE 中的作用。最后，在目标 4 中，我们将研究维生素 A 的饮食控制如何影响 EAE 中 DGAT1 缺乏的影响。结果这一目标可能为多发性硬化症患者补充维生素 A 提供机制依据，因为维生素 A 水平较低 A 与疾病风险增加相关，血清视黄醇水平与磁性呈负相关 MS 中的共振成像结果。总之，拟议的研究有望阐明 T 细胞免疫代谢和 DGAT1 在驱动 MS 疾病发病机制中的作用，并具有减少 MS 疾病发病机制的巨大转化潜力多发性硬化症对美国退伍军人、他们的家人和美国公众的影响。