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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（MS）是中枢神经系统（CNS）的使人衰弱的脱髓鞘疾病，影响了全球约250万人。美国军事人员面临着发展MS的特殊风险：美国军人的发病率（12.9/100，000人年）是平民的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）是一种 EAE和MS中的组织损伤是由EAE和MS引起的，炎症性白细胞进入中枢神经系统破坏髓鞘CNS浸润性髓鞘反应性CD 4 + T细胞细胞在MS的病理学中起着关键作用。尽管许多MS治疗是可用的，但由于MS的病理学特征， MS疾病过程的异质性，个体患者的反应和药物毒性，对改进的治疗剂的大量未满足的临床需求。 T细胞分化和功能受到代谢途径类维生素A的参与的深刻影响处理.二酰基甘油O-酰基转移酶-1（DGAT 1）是一种代谢酶，可以催化甘油二酯的合成。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DGAT 1在T细胞生物学中的作用知之甚少。我们的初步研究表明 DGAT 1在体外和体内EAE期间在活化的小鼠CD 4 + T细胞中选择性上调。 DGAT 1选择性地在脑病变和从MS患者获得的CD 4+血液T细胞中表达。DGAT1 保护KO小鼠免受EAE，并且DGAT 1药物抑制抑制EAE。基于我们初步数据和维甲酸代谢的重要性，在管理T细胞分化和功能，我们假设T细胞表达DGAT 1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的1中，我们将研究用小分子拮抗剂靶向DGAT 1的翻译效用，治疗脱髓鞘疾病。我们将检验人血CD 4 + T细胞表达DGAT 1和含有DGAT/ARAT活性，并且DGAT 1调节Treg和Th 17分化和功能。我们将还检验了疾病发作后给予DGAT 1抑制剂将逆转EAE进展的假设防止复发值得注意的是，小分子DGAT 1抑制剂已经在临床试验中进行了测试，肥胖相关疾病的治疗。因此，目标1中的研究可能会发现新的MS特异性已通过I期安全性研究的现有药物的申请。在目标2中，我们建议定义 DGAT 1在CD 4+效应T细胞形成和功能中的作用。使用体外极化的CD 4 + T细胞，我们将定义小鼠Treg和Th 17细胞中DGAT 1表达和ARAT活性。使用来自WT的初始T细胞和来自 DGAT 1 KO小鼠，我们将定义DGAT 1在Treg和Th 17分化和功能中的作用。以促进为了研究DGAT 1在Treg发育中作用，我们提出了DGAT 1 KO/Foxp 3/GFP小鼠（DGAT 1 KO 用GFP+ TGFP的小鼠）。在目标3中，我们提出了产生T细胞条件诱导型DGAT 1 KO小鼠（CD 4CreERT 2-DGAT 1fl/fl）来确定T细胞表达的DGAT 1在EAE中的作用。最后，在目标4中，研究维生素A的饮食操作如何影响EAE中DGAT 1缺乏的影响。结果从这个目的可能提供了一个机械原理维生素A补充MS，因为低水平的维生素A， A与疾病风险增加有关，血清视黄醇水平与磁场强度呈负相关。多发性硬化症的共振成像结果。总之，拟议的研究有望阐明T细胞免疫代谢的新见解， DGAT 1在MS中驱动疾病发病机制中的作用，并具有巨大的翻译潜力，以减少 MS对美国退伍军人，他们的家庭和美国公众的影响。