Neuroprotective role of vitamin D during childhood

摘要 多发性硬化(MS)是一种中枢神经系统(CNS)炎性脱髓鞘疾病 这会导致进行性神经功能障碍，影响到美国的40万人。2007年，MS总成本 在美国超过200亿美元，今天如果美国每个多发性硬化症患者每年花费180亿美元 只用了一种治疗疾病的药物，更不用说生产力损失和 其他医疗护理。多发性硬化症的病因仍不清楚；人们普遍认为，遗传因素的结合 而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 MS的重要环境风险尚不清楚的是，早期维生素D缺乏如何影响 多发性硬化症的易感性以前的研究表明，多发性硬化症患者血清维生素D水平较高是 与较低的复发风险有关，这与其免疫调节功能一致。不过，这个 维生素D的免疫调节活性不能解释中枢神经系统特异性自身免疫性疾病的发生。一个 高维生素D饮食可减弱小胶质细胞的激活并减少脱髓鞘，提示有神经保护作用 维生素D的作用白介素34(IL-34)最近被证明对体内平衡是必不可少的 小胶质细胞。IL-34由中枢神经系统神经元产生，其表达在出生后达到高峰 成年后发育衰退，维生素D可以积极调节IL-34的表达。团结在一起， IL-34的表达时机/模式和功能使其成为维生素D介导的首选候选分子 神经保护分子，这可能最终有助于降低MS的敏感性。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印记保护作用的机制 在生命的后期对多发性硬化症的发展不利。该项目的总体目标是使用转基因小鼠。 -神经元特异性可诱导维生素D受体基因敲除小鼠阐明维生素D信号如何受损 早期生命中的神经元改变了小胶质细胞的表型。我们的主要假设是维生素D启动了小胶质细胞 通过促进神经元产生IL-34和/或其他因子进入神经保护表型 在一个发展中的中枢神经系统。这项研究的理论基础是，一旦早期生命与维生素D的相关性 缺乏症和多发性硬化症易感性得到了充分的定义，这将是制定公共卫生政策的基础 目的是：1)阐明IL-34在多发性硬化症中的功能作用 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 在早期生命感染期间中枢神经系统的反应，以及3)确定早期生命中是否存在维生素D不足 增加多发性硬化症的动物模型EAE的易感性这些结果将有重要的积极意义 影响，因为它们将定义维生素D介导的早期生命神经保护的细胞机制。 了解环境因素如何影响多发性硬化症风险将是迈向终极目标的重要一步 目标--预防多发性硬化。

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.