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不足是多发性硬化症（MS）的一个已知易感因素，但尚不确定它是否也影响已患有该疾病的个体的预后。虽然在MS动物模型中补充维生素D可以改善临床结果，但缺乏设计良好的人类研究。最近在HLA-DRB 1 *15的启动子区域中鉴定了维生素D反应元件，该基因被认为是启动MS中自身免疫反应的关键，并且维生素D在体外增加该基因的表达。这些发现表明，维生素D补充剂甚至可能对已建立的MS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补充剂的MS患者可能无法达到血清25-羟基维生素D3水平的预期增加，维生素D代谢关键酶的多态性与MS风险增加相关，表明潜在的药代动力学差异。我们建议利用一个大型的、现存的MS队列，前瞻性地收集临床和成像数据，每年采集一次，持续5年，以确定维生素D状态是否与随后的临床或脑MRI证据有关，这些证据表明炎症活动增加或神经退行性变加速，我们还将进行一项补充维生素D的初步研究，以评估药物代谢动力学或免疫反应是否在MS患者和健康受试者中存在差异。最后，我们将评估维生素D水平和补充剂与HLA-DRB 1和HLA-DRB 5表达的相关性，这与MS表型相关。这一可行且具有成本效益的项目将为未来MS中维生素D的机制研究和精心设计的临床试验提供理论依据。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在先进的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，所有这些我需要建立自己作为一个独立的临床研究人员在MS我的长期目标是整合这些学科，以确定可修改的环境预后因素在MS和探索的机制，通过它们影响其过程。加州大学旧金山分校弗朗西斯科的硕士课程由临床、神经影像学、遗传学和免疫学研究人员组成的合作网络组成，他们将提供一个丰富的环境，我将在其中进行拟议的职业发展和研究计划。

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.