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）是一种令人衰弱的中枢神经系统（CNS）的脱髓鞘疾病全球约有250万人影响。美国军事人员有特殊风险发展MS：美国军人的发病率（每100,000人年12.9）比平民高1.7倍人口，比全球人口高3倍。实验性自身免疫性脑脊髓炎（EAE）是广泛研究的动物模型具有人类MS的许多特征。 EAE和MS引起的组织损伤通过进入中枢神经系统并破坏髓鞘的炎症性白细胞。 CNS浸润，髓磷脂反应性CD4+ T 细胞在MS的病理中起关键作用。尽管有许多MS治疗可用，但由于 MS疾病过程，个体患者反应和药物毒性的异质性，有一个对改善治疗剂的重大未满足的临床需求。 T细胞的分化和功能受到代谢途径的参与性的深刻影响加工。二酰基甘油O-酰基转移酶-1（DGAT1）是一种代谢酶，可以催化甘油三酸酯（TG，通过DGAT活性）和视黄酯的合成（RE，通过酰基COA：视黄醇酰基转移酶（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，在活化的小鼠CD4+ T细胞中，该DGAT1在活化的小鼠CD4+ T细胞中被选择性上调。 DGAT1在脑病变和从MS患者中获得的CD4+血液T细胞有选择性表达。 DGAT1 KO小鼠受到保护，不受EAE的保护，DGAT1药物抑制作用抑制了EAE。基于我们初步数据以及类维生素性代谢在治理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AIM 1中，我们将研究用小分子拮抗剂靶向DGAT1的翻译实用性治疗脱髓鞘疾病。我们将测试人类血液CD4+ T细胞表达DGAT1和包含DGAT/ARAT活性，并且DGAT1调节Treg和Th17的分化和功能。我们将还测试了以下假设：疾病发作后施用的DGAT1抑制剂将反向EAE进展并防止复发。值得注意的是，在临床试验中已经测试了小分子DGAT1抑制剂的肥胖相关疾病的治疗。因此，AIM 1中的研究可能会发现新的MS特异性现有药物已经清除了I期安全研究的申请。在AIM 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的幼稚T细胞， DGAT1 KO小鼠，我们将定义DGAT1在Treg和Th17分化和功能中的作用。促进 DGAT1在Treg开发中的研究，我们建议生成DGAT1 KO/FOXP3/GFP小鼠（DGAT1 KO 带有GFP+ Tregs的小鼠）。在AIM 3中，我们建议生成T细胞条件诱导DGAT1 KO小鼠（CD4CREERT2 -DGAT1FL/FL）定义T细胞表达DGAT1在EAE中的作用。最后，在目标4中，我们将研究维生素A的饮食操纵如何影响DGAT1缺乏症对EAE的影响。结果从此目的可以为MS中的维生素A补充提供机械原理，因为维生素水平较低 A与疾病风险增加有关，血清视黄醇水平与磁性成反比共振成像结果在MS中。拟议的研究共同有望阐明对T细胞免疫代谢的新洞察力和 DGAT1在驱动MS疾病发病机理中的作用，并具有巨大的翻译潜力来减少女士对美国退伍军人，他们的家人和美国公众的影响。