Metabolic correlates of disease activity and disability progression in pediatric MS

项目摘要 导致多发性硬化症（MS）复发和残疾进展的生物学过程仍然存在 大部分未知。在过去的十年中，我们的儿科MS网络调查了儿童的风险因素。我们 他们发现，高饱和脂肪和低蔬菜饮食摄入量可能独立地增加 复发的风险。我们的初步研究结果，与高脂肪饮食的关联一致 MS复发风险较高，表明三种酰基乙醇酰胺的血浆水平较高， （内源性大麻素）和二十二碳六烯酸（DHA）可能与儿童复发风险较高有关。 脂质介质如氧脂素和内源性大麻素具有免疫调节特性，并且一些具有免疫调节特性。 神经保护他们的血浆水平受饮食摄入、肥胖状况和遗传因素等的影响。 profile.此外，我们发现色氨酸途径与复发和疾病的风险有关， 进展与我们计划研究的短链脂肪酸的预期变化有着必然的联系。 虽然MS在儿童中不太常见，但在该年龄组中进行的研究具有几个重要的优势，包括 减少不相关的暴露和老化导致的合并症。与以前的NIH和国家MS协会 在支持下，我们建立了一个高度合作的国家研究小组和一个独特的资源， 在这个提案中利用来测试新的假设。我们建议采用最先进的非目标性和目标性 代谢组学和脂质组学分析，以确定各种血浆和粪便脂质及其 具有随后复发、新MRI病变以及神经和认知障碍风险的介质。每个 个体具有广泛的人口统计学、临床、MRI、遗传、食物频率和环境暴露数据。 分析将根据可能的混杂因素进行调整，如年龄、性别、人种、种族、社会经济学特征、使用 疾病改善治疗，体重指数和血清25（OH）维生素D。我们还将模拟贡献 在脂肪因子、食物频率、肠道微生物组谱和遗传变异的背景下， 调节血浆脂质和介质水平。包括路径分析在内的复杂建模将 确定哪些变量是独立预测变量。 我们的合作者团队在代谢组学，脂质组学，遗传学和环境风险因素方面具有专业知识 是在一个独特的位置，以显着推进MS发病机制的理解。中的调查结果 拟议的研究将揭示饮食，肠道微生物组，肥胖和MS课程之间的生物学联系。虽然 纵向关联研究不能证实因果关系，但对于确定假定的生物学途径至关重要 可能导致疾病活动和进展。干预研究不能设计，如果协会 是未知的。我们提出的研究具有很强的临床转化潜力，因为我们将确定生物学 然后可以在概念验证MS试验中测试因果关系的目标， 补充影响感兴趣的代谢途径的活生物活性物质产品。

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.