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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：
10427137
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/10427137
关键词：
Active Immunization Acyl Coenzyme A Acyltransferase Affect All-Trans-Retinol American Animal Model Animals Autoimmune 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 Toxic effect Triglycerides Veterans Vitamin A antagonist 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 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 tissue injury translational potential

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）是一种中枢神经系统（CNS）的衰弱性脱髓鞘疾病