Metabolic correlates of disease activity and disability progression in pediatric MS

儿科多发性硬化症疾病活动性和残疾进展的代谢相关性

基本信息

批准号：
10593945
负责人：
EMMANUELLE LAURENCE WAUBANT
金额：
$ 27.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593945
关键词：
16S ribosomal RNA sequencing Adult Affect Age Aging Animal Model Anti-Inflammatory Agents Biological Biological Process Biological Response Modifier Therapy Blood Body mass index Child Childhood Clinical Complex Cox Proportional Hazards Models Data Diet Dietary Fiber Dietary intake Digit structure Disease Disease Marker Disease Outcome Disease Progression Disease model Docosahexaenoic Acids Dyslipidemias Endocannabinoids Energy Metabolism Environmental Exposure Environmental Risk Factor Ethnic Origin Etiology Experimental Autoimmune Encephalomyelitis Fatty Acids Fatty acid glycerol esters Feces Fermentation Food Frequencies Functional disorder Future Genetic Goals High Fat Diet Immune response Impaired cognition In Vitro Individual Inflammation Inflammation Mediators Inflammatory Injury Intake Intervention Intervention Studies Intervention Trial Investigation Isotope Labeling Least-Squares Analysis Lesion Link Lipids Lipoxygenase Liquid Chromatography Literature Magnetic Resonance Imaging Mass Fragmentography Measures Mediation Mediator Metabolic Metabolic Pathway Modality Modeling Multiple Sclerosis Multivariate Analysis Neurologic Obesity Pathogenesis Pathway Analysis Pathway interactions Peripheral Plasma Positioning Attribute Property Propionates Race Regression Analysis Regulation Relapse Reporting Research Resources Risk Risk Factors Serum Signaling Molecule Societies Supplementation Testing Tryptophan Tryptophan Metabolism Pathway United States National Institutes of Health Vegetables Vitamin D Volatile Fatty Acids adipokines age group biobank clinical translation cognitive change cognitive disability comorbidity data integration data reduction design disability effective therapy forest genetic makeup genetic risk factor genetic variant gut metagenome gut microbiome high risk immunoregulation inflammatory marker interest lipid mediator lipidomics machine learning algorithm metabolome metabolomics multiple sclerosis patient neuroprotection pediatric multiple sclerosis pediatric patients physically handicapped relapse risk saturated fat sex socioeconomics stool sample tandem mass spectrometry tool treatment strategy

项目摘要

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.

项目概要导致多发性硬化症 (MS) 复发和残疾进展的生物过程仍然存在很大程度上不为人知。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该疾病的人有复发的风险。我们的初步研究结果与高脂肪饮食的关联一致多发性硬化症复发的风险较高，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）可能与儿童较高的复发风险有关。脂质介质如氧脂质和内源性大麻素具有免疫调节特性，其中一些是神经保护作用。他们的血浆水平受到饮食摄入量、肥胖状况和遗传等因素的影响轮廓。此外，我们发现色氨酸途径与复发和疾病的风险相关进展似乎与我们计划研究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较少见，但针对该年龄段的研究有几个重要的优势，包括减少因衰老而导致的不相关的暴露和合并症。与之前的 NIH 和国家多发性硬化症协会合作支持，我们建立了一个高度协作的国家研究小组和一个独特的资源，将在此提案中利用它来测试新的假设。我们提出最先进的无针对性和有针对性的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关联具有随后复发、新 MRI 病变以及神经和认知障碍风险的介质。每个个人拥有广泛的人口统计、临床、MRI、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，例如年龄、性别、种族、民族、社会经济状况、用途疾病缓解治疗、体重指数和血清 25(OH) 维生素 D 的影响。我们还将对贡献进行建模脂肪因子、食物频率、肠道微生物组概况和遗传变异背景下的各种代谢物调节血浆脂质和介质水平。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的预测变量。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拥有专业知识在显着推进对多发性硬化症发病机制的理解方面处于独特的地位。研究结果在拟议的研究将揭示饮食、肠道微生物组、肥胖和多发性硬化症病程之间的生物学联系。虽然纵向关联研究并不能证实因果关系，但它们对于确定假定的生物学途径至关重要这可能会导致疾病活动和进展。如果存在关联，则无法设计干预研究未知。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 试验中通过以下干预措施来测试目标的因果关系：补充影响感兴趣的代谢途径的活生物治疗产品。