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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS067055-04
Application #
8470724
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2010-06-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$193,023
Indirect Cost
$14,298
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
University of California, San Francisco MS-EPIC Team:; Cree, Bruce A C; Gourraud, Pierre-Antoine et al. (2016) Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol 80:499-510
Sotirchos, Elias S; Bhargava, Pavan; Eckstein, Christopher et al. (2016) Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology 86:382-90
Mowry, E M; Pelletier, D; Gao, Z et al. (2016) Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol 23:327-32
Bhargava, Pavan; Steele, Sonya U; Waubant, Emmanuelle et al. (2016) Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. Mult Scler 22:753-60
Cantarel, Brandi L; Waubant, Emmanuelle; Chehoud, Christel et al. (2015) Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med 63:729-34
Waubant, Emmanuelle; Mowry, Ellen M; Krupp, Lauren et al. (2013) Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. Mult Scler 19:891-5
Tan, Ik Lin; Mowry, Ellen M; Steele, Sonya U et al. (2013) Brainstem encephalitis: etiologies, treatment, and predictors of outcome. J Neurol 260:2312-9
von Geldern, Gloria; Mowry, Ellen M (2012) The influence of nutritional factors on the prognosis of multiple sclerosis. Nat Rev Neurol 8:678-89
Fay, Alex J; Mowry, Ellen M; Strober, Jonathan et al. (2012) Relapse severity and recovery in early pediatric multiple sclerosis. Mult Scler 18:1008-12
Mowry, Ellen M; Waubant, Emmanuelle; McCulloch, Charles E et al. (2012) Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 72:234-40

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