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

描述(由申请人提供)：维生素D缺乏是多发性硬化症(MS)的已知易感因素，但尚不确定它是否也会影响已经患有这种疾病的个人的预后。虽然在多发性硬化症的动物模型中补充维生素D可以改善临床结果，但在人类中缺乏精心设计的研究。最近在人类白细胞抗原-DRB1*15的启动子区域发现了一个维生素D反应元件，该基因被认为是启动MS自身免疫反应的关键基因，维生素D在体外增加了该基因的表达。这些发现表明，补充维生素D甚至可能对已确诊的多发性硬化症有害。虽然医生团体开始倡导广泛补充维生素D，但最合适的维生素D剂量尚不清楚。接受口服维生素D补充的MS患者可能无法达到预期的血清25-羟基维生素D3水平的增加，维生素D代谢中的一个关键酶的多态性与MS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，利用五年内每年收集的前瞻性临床和成像数据，确定维生素D状态是否与随后的临床或脑MRI证据有关，即炎症活动增加或加速神经变性，这是多发性硬化症的两个关键病理过程。我们还将进行一项补充维生素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不同。最后，我们将评估维生素D水平和补充剂与与MS表型相关的人类白细胞抗原-DRB1和人类白细胞抗原-DRB5表达的相关性。这一可行且具有成本效益的项目将为未来维生素D在多发性硬化症中的机制研究和精心设计的临床试验提供理论基础。多发性硬化症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、遗传学和神经成像方面的培训，所有这些我都需要确立自己作为多发性硬化症独立临床研究人员的地位。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，并探索它们影响多发性硬化症进程的机制。加州大学旧金山分校的MS项目由临床、神经成像、遗传学和免疫学研究人员组成的协作网络组成，他们将提供一个丰富的环境，我将在其中实施拟议的职业发展和研究计划。 公共卫生相关性：多发性硬化症在美国至少影响40万人，是年轻人神经功能障碍的主要原因。这项研究将确定维生素D不足是否与更糟糕的疾病结局有关。它还将确定多发性硬化症患者是否需要与健康人相同剂量的维生素D，以达到足够的血液水平，并探索维生素D可能对多发性硬化症患者起重要作用的机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Multiple sclerosis affects at least 400,000 people in the United States lone and is a major cause of neurologic disability in young adults. This study will establish if vitamin D insufficiency is associated with worse disease outcomes. It will also determine if multiple sclerosis patients need the same dose of vitamin D as healthy individuals to achieve an adequate blood level and explore mechanisms by which vitamin D may be important in multiple sclerosis patients.