The effect of vitamin D on the clinical and imaging course of multiple sclerosis

维生素D对多发性硬化症临床及影像学过程的影响

• 批准号: 8295085
• 负责人: Ellen M. Mowry
• 金额: $ 16.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295085
• 关键词: Advocate; Affect; Animal Model; Autoimmune Responses; Biometry; Blood; Brain; Calcifediol; California; Clinical; Clinical Trials Design; Complex; Data; Development Plans; Discipline; Disease; Disease Outcome; Dose; Drug Kinetics; Environment; Enzymes; Epidemiology; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Goals; HLA-DRB1; Human; Image; Immunologics; Immunology; In Vitro; Individual; Inflammatory; Magnetic Resonance Imaging; Metabolism; Multiple Sclerosis; Nerve Degeneration; Neurologic; Oral; Outcome; Pathologic Processes; Patients; Phenotype; Physicians; Pilot Projects; Predisposition; Prognostic Factor; Promoter Regions; Research Design; Research Personnel; Risk; San Francisco; Serum; Supplementation; Training; United States; Universities; Vitamin D; Vitamin D Response Element; career development; chronic neurologic disease; cohort; cost effective; disability; improved; neuroimaging; nutrition; outcome forecast; programs; research and development; response; young adult

Vitamin D insufficiency is a known susceptibility factor for multiple sclerosis (MS), but it is uncertain if it also influences the prognosis of individuals who already have the disease. While vitamin D supplementation in the animal model of MS improves clinical outcomes, well-designed studies in humans are lacking. A vitamin D response element was recently identified in the promoter region of HLA-DRB1*15, the gene believed to be critical to initiating the autoimmune response in MS, and vitamin D increases the expression of the gene in vitro. These findings suggest that vitamin D supplementation could even be harmful in established MS. While physician groups are beginning to advocate for widespread vitamin D supplementation, the most appropriate vitamin D dose is not known. Patients with MS who receive oral vitamin D supplementation may not attain the expected increase in serum 25-hydroxyvitamin D3 levels, and a polymorphism in a key enzyme in vitamin D metabolism is associated with increased MS risk, suggesting potential pharmacokinetic differences. We propose to capitalize on a large, extant MS cohort with prospectively-collected clinical and imaging data acquired annually for five years to determine if vitamin D status is associated with subsequent clinical or brain MRI evidence of increased inflammatory activity or accelerated neurodegeneration, two key pathologic processes in MS. We will also conduct a pilot study of vitamin D supplementation to assess if the pharmacokinetic or immunologic response differs in MS patients and healthy subjects. Finally, we will evaluate the association of vitamin D levels and supplementation with the expression of HLA-DRB1 and HLA-DRB5, which have been correlated with MS phenotype. This feasible and cost-effective project will provide rationale for future mechanistic studies of vitamin D in MS and for well-designed clinical trials. MS is a complex chronic neurologic disease, the study of which requires the integration of many disciplines. My career development plan includes training in advanced biostatistics and epidemiology, nutrition, immunology, genetics and neuroimaging, all of which I need to establish myself as an independent clinical researcher in MS. My long-term goal is to integrate these disciplines to identify modifiable environmental prognostic factors in MS and to explore the mechanisms by which they influence its course. The MS program at the University of California, San Francisco consists of a collaborative network of clinical, neuroimaging, genetics, and immunology researchers who will provide a rich environment in which I will conduct the proposed career development and research plans.

维生素 D 不足是已知的多发性硬化症 (MS) 易感因素，但尚不确定它是否也会影响已患有该疾病的个体的预后。虽然多发性硬化症动物模型中补充维生素 D 可改善临床结果，但缺乏精心设计的人体研究。最近在 HLA-DRB1*15 的启动子区域发现了维生素 D 反应元件，该基因被认为对于启动多发性硬化症的自身免疫反应至关重要，维生素 D 可以增加该基因的体外表达。这些研究结果表明，补充维生素 D 甚至可能对已确诊的多发性硬化症有害。虽然医生团体开始提倡广泛补充维生素 D，但最合适的维生素 D 剂量尚不清楚。接受口服维生素 D 补充剂的多发性硬化症患者可能无法达到预期的血清 25-羟基维生素 D3 水平增加，并且维生素 D 代谢中关键酶的多态性与多发性硬化症风险增加相关，这表明潜在的药代动力学差异。我们建议利用现有的大型多发性硬化症队列，每年前瞻性收集临床和影像数据，为期五年，以确定维生素 D 状态是否与随后的临床或脑部 MRI 证据表明炎症活动增加或神经变性加速（这是多发性硬化症的两个关键病理过程）相关。我们还将开展一项补充维生素 D 的试点研究，以评估多发性硬化症患者和健康受试者的药代动力学或免疫学反应是否存在差异。最后，我们将评估维生素 D 水平和补充剂与 HLA-DRB1 和 HLA-DRB5 表达的关系，这些表达与 MS 表型相关。这一可行且具有成本效益的项目将为维生素 D 在多发性硬化症中的未来机制研究和精心设计的临床试验提供依据。 MS是一种复杂的慢性神经系统疾病，其研究需要多学科的整合。我的职业发展计划包括高级生物统计学和流行病学、营养学、免疫学、遗传学和神经影像学方面的培训，所有这些都是我需要使自己成为多发性硬化症独立临床研究员的培训。我的长期目标是整合这些学科，以确定多发性硬化症中可改变的环境预后因素，并探索它们影响其病程的机制。加州大学旧金山分校的 MS 项目由临床、神经影像、遗传学和免疫学研究人员组成的协作网络组成，他们将为我开展拟议的职业发展和研究计划提供丰富的环境。