Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes progressive neurological deficits, which affects 400,000 people in the USA. In 2007, total MS costs in the USA exceeded $20 billion, and today it would cost $18 billion per year if every MS patient in the USA was treated with just one disease modifying drug, not to mention the additional costs of lost productivity and other medical care. The cause of MS remains unknown; it is generally accepted that the combination of genetic and environmental factors determines the disease susceptibility. Vitamin D deficiency is emerging as an important environmental risk of MS. What is not known is how early life vitamin D deficiency influences the susceptibility to MS. Previous studies have shown that higher serum vitamin D levels in MS patients are associated with lower risk of relapse, in agreement with its immune-modulatory functions. However, this immune-regulatory activity of vitamin D does not explain the onset of a CNS-specific autoimmune disease. A high vitamin D diet attenuates microglia activation and reduces demyelination, suggesting a neuroprotective role of vitamin D. Interleukin-34 (IL-34) has recently been shown to be essential for the homeostasis of microglia. IL-34 is produced by neurons in the CNS, and its expression reaches its peak during postnatal development then declines in adulthood and vitamin D can positively regulate IL-34 expression. Together, the expression timing/pattern and functions of IL-34 make it a prime candidate as a vitamin D-mediated neuroprotective molecule, which may ultimately contribute to decreased MS susceptibility. The longterm goal of this study is to understand the mechanism by which sufficient vitamin D in early life imprints the protection against MS development later in life. The overall objective of the proposed project is to use a transgenic mouse - neuron-specific inducible vitamin D receptor knockout mice to elucidate how impaired vitamin D signaling on neurons during early life alters microglia phenotypes. Our main hypothesis is that vitamin D primes microglia into the neuroprotective phenotype through enhancing the production of IL-34 and/or other factors in neurons in a developing CNS. The rationale that underlies this study is that, once the correlation of early life vitamin D deficiency and MS susceptibility is fully defined, this will be the foundation for making a public health policy to manipulate this easily modifiable risk factor for MS.
The aims are: 1) Elucidate the functional role of IL-34 in vitamin D-mediated neuroprotection, 2) determine if vitamin D modulates IL-34 and inflammatory cytokine responses in the CNS during early life infection, and 3) determine if vitamin D insufficiency in early life enhances susceptibility to EAE, an animal model of MS. These outcomes will have an important positive impact because they will define the cellular mechanism of vitamin D-mediated neuroprotection in early life. Understanding how this environmental factor influence MS risks will be a significant step towards the ultimate goal - prevent MS.

Public Health Relevance

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes progressive neurological deficits, affecting 400,000 people in the USA with an annual cost of exceeding $20 billion. The prevalence and incidence of MS are on the increase worldwide, necessitating strategies to prevent MS. This study will have an important positive impact because it will define the cellular mechanism of vitamin D-mediated neuroprotection in early life. Understanding how this environmental factor influences MS risk will be a significant step towards the ultimate goal - prevent MS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD086368-02
Application #
9331716
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Krotoski, Danuta
Project Start
2016-08-15
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210