Neuroprotective role of vitamin D during childhood

摘要 多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病 会导致进行性神经功能缺损，在美国有40万人受到影响。2007年，管理事务费用总额 超过200亿美元，而今天，如果美国的每一位MS患者每年花费180亿美元， 仅仅用一种疾病修饰药物治疗，更不用说生产力损失的额外费用， 其他医疗护理。MS的原因仍然未知;人们普遍认为，遗传因素的组合 环境因素决定了疾病的易感性。维生素D缺乏症正在成为一种 目前尚不清楚的是，早期维生素D缺乏如何影响 以前的研究表明，MS患者血清维生素D水平较高， 与较低的复发风险相关，与其免疫调节功能一致。但这 维生素D的免疫调节活性不能解释CNS特异性自身免疫性疾病的发病。一 高维生素D饮食可减弱小胶质细胞活化并减少脱髓鞘，这表明 维生素D的作用白细胞介素-34（IL-34）最近已被证明是必不可少的稳态， 小胶质细胞IL-34由中枢神经系统的神经元产生，其表达在出生后达到高峰 发育然后在成年期下降，维生素D可以积极调节IL-34的表达。统称 IL-34的表达时间/模式和功能使其成为维生素D介导的免疫调节的主要候选者。 神经保护分子，其可能最终有助于降低MS易感性。长期目标 这项研究的目的是了解早期生命中充足的维生素D对保护作用的机制。 在以后的生活中预防MS的发展。拟议项目的总体目标是使用转基因小鼠 - 神经元特异性可诱导的维生素D受体敲除小鼠，以阐明受损的维生素D信号如何在 神经元在生命早期改变小胶质细胞表型。我们的主要假设是维生素D引发小胶质细胞 通过增强神经元中IL-34和/或其他因子的产生而转化为神经保护表型 在发育中的中枢神经系统中这项研究的基本原理是，一旦生命早期维生素D的相关性 缺乏症和MS易感性得到充分定义，这将是制定公共卫生政策的基础， 目的是：1）阐明IL-34在MS中的功能作用， 维生素D介导的神经保护，2）确定维生素D是否调节IL-34和炎性细胞因子 在生命早期感染期间CNS的反应，以及3）确定生命早期维生素D不足是否 增强对EAE的易感性，这是一种MS的动物模型。这些结果将具有重要的积极意义。 因为它们将定义生命早期维生素D介导的神经保护的细胞机制。 了解这一环境因素如何影响MS风险将是迈向最终目标的重要一步。 目标-预防MS。

Abstract 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.