Metabolic correlates of disease activity and disability progression in pediatric MS

项目总结 多发性硬化症(MS)复发和残疾进展的生物学过程仍然存在 很大程度上是未知的。在过去的十年中，我们的儿科多发性硬化症网络调查了儿童的危险因素。我们 研究发现，较高的饱和脂肪和较低的蔬菜饮食摄入量可能独立地增加 患有这种疾病的人有复发的风险。我们的初步发现，与高脂肪饮食的联系一致 MS复发风险较高，提示血浆中三种酰乙醇胺水平较高 (内源性大麻素)和二十二碳六烯酸(DHA)可能与儿童较高的复发风险有关。 脂类介体，如氧磷脂和内源性大麻素，具有免疫调节特性，有些 具有神经保护作用。他们的血浆水平受饮食摄入量、肥胖状况和遗传因素的影响。 侧写。此外，我们的发现，色氨酸途径与复发和疾病的风险有关 进展似乎与我们计划调查的短链脂肪酸的预期变化有关。 尽管多发性硬化症在儿童中不太常见，但在这个年龄段进行研究有几个重要的优势，包括 不太相关的暴露和衰老引起的并存。与之前的NIH和国家多发性硬化症学会 支持，我们已经建立了一个高度协作的国家研究小组和一个独特的资源，将是 在这项提议中被用来测试新的假设。我们提出了最先进的无目标和有目标 代谢组学和脂类组学分析以确定各种血浆和大便脂质及其相互关系 有复发风险的介体，新的核磁共振损伤，以及神经和认知障碍。每个人 个人拥有广泛的人口统计、临床、核磁共振、遗传、食物频率和环境暴露数据。 分析将针对可能的混杂因素进行调整，如年龄、性别、种族、民族、社会经济概况、使用 疾病修正疗法、体重指数和血清25(OH)维生素D。我们还将模拟这些贡献 不同代谢物在脂肪因子、食物频率、肠道微生物群谱和遗传变异方面的关系 调节血脂和介质水平的物质。这种包括路径分析在内的复杂模型将 确定哪些变量是独立预测因素。 我们的团队在代谢组学、脂类组学、遗传学和环境风险因素方面具有专业知识 在极大地促进对MS发病机制的理解方面处于独特的地位。报告中的研究结果 拟议的研究将揭开饮食、肠道微生物群、肥胖和多发性硬化症病程之间的生物学联系。虽然 纵向关联研究不能确认因果关系，但它们对确定假定的生物学途径至关重要。 这可能有助于疾病的活动和进展。如果存在关联，就不能设计干预研究 都是未知的。我们提议的研究具有很强的临床翻译潜力，因为我们将识别生物学 目标，然后可以在概念验证MS试验中通过干预进行因果关系测试，例如 补充活的生物治疗产品会影响感兴趣的代谢途径。

PROJECT SUMMARY The biological processes contributing to relapses and disability progression in multiple sclerosis (MS) remain largely unknown. During the past decade, our pediatric MS Network has investigated risk factors in children. We have discovered that higher saturated fat and lower vegetable dietary intake may independently increase the risk of relapse in those with the disease. Our preliminary findings, consistent with the association of high fat diet with higher risk of MS relapse, suggest that higher plasma levels of three acyl-ethanolamides (endocannabinoids) and docosahexaenoic acid (DHA) may be associated with higher relapse risk in children. Lipids mediators such as oxylipins and endocannabinoids have immunomodulatory properties and some are neuroprotective. Their plasma levels are influenced among others by dietary intake, obesity status and genetic profile. Furthermore, our findings that the tryptophan pathway is associated with the risk of relapse and disease progression links plausibly to expected changes in short chain fatty acids that we plan to investigate. Although MS is less common in children, studies in this age group have several important advantages including less irrelevant exposures and comorbidities that result from aging. With previous NIH and National MS Society support, we have established a highly collaborative national research group and a unique resource that will be leveraged in this proposal to test new hypotheses. We propose state-of-the-art untargeted and targeted metabolomics and lipidomics analyses to determine the association of various plasma and stool lipids and their mediators with the risk of subsequent relapse, new MRI lesions, and neurologic and cognitive impairment. Each individual has extensive demographic, clinical, MRI, genetic, food frequency and environmental exposure data. Analyses will be adjusted for possible confounders such as age, sex, race, ethnicity, socioeconomic profile, use of disease-modifying therapy, body mass index and serum 25(OH) vitamin D. We will also model the contribution of various metabolites in the context of adipokines, food frequency, gut microbiome profile and genetic variants that modulate plasma lipid and mediator levels. This sophisticated modelling including pathway analyses will establish which of the variables are independent predictors. Our group of collaborators with expertise in metabolomics, lipidomics, genetics, and environmental risk factors is in a unique position to significantly advance the understanding of MS pathogenesis. The findings in the proposed study will unravel biological links between diet, gut microbiome, obesity and MS course. Although longitudinal association studies do not confirm causality, they are critical to identify putative biological pathways that may contribute to disease activity and progression. Intervention studies cannot be designed if associations are unknown. Our proposed investigation has strong potential for clinical translation as we will identify biological targets that can then be tested for causality in proof-of-concept MS trials with interventions such as supplementation with live biotherapeutic products influencing metabolic pathways of interest.