Neuroprotective role of vitamin D during childhood

维生素 D 在儿童时期的神经保护作用

基本信息

批准号：
9331716
负责人：
Amy E Lovett-Racke
金额：
$ 19.25万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331716
关键词：
Ablation Adult Affect Agreement Alleles Animal Model Anti-Inflammatory Agents Anti-inflammatory Attenuated Autoimmune Diseases Caring Characteristics Childhood Cuprizone Demyelinations Development Diet Disease Disease Progression Disease susceptibility Environmental Risk Factor Experimental Autoimmune Encephalomyelitis Exposure to Foundations Frequencies Genetic Goals Health Policy Healthcare Systems Homeostasis Immune Impairment Incidence Infection Inflammatory Inflammatory Response Pathway Interleukins Knockout Mice Knowledge Life Link Mediating Medical Microglia Modeling Multiple Sclerosis Multiple Sclerosis Lesions Mus Neuraxis Neurologic Deficit Neurons Onset of illness Outcome Pattern Pharmaceutical Preparations Phenotype Predisposition Prevalence Production Productivity Property Public Health Reporting Rest Risk Risk Factors Role Serum Signal Transduction Societies Sun Exposure Sunlight T-Lymphocyte Time Transgenic Mice Vitamin D Vitamin D Deficiency Vitamin D3 Receptor central nervous system demyelinating disorder cost cytokine epidemiology study imprint in vivo innovation migration modifiable risk multiple sclerosis patient neuroprotection postnatal prevent relapse risk

项目摘要

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.

抽象的多发性硬化症（MS）是一种炎症性脱髓鞘疾病（CNS）这会导致渐进性神经缺陷，影响美国40万人。在2007年，MS总成本在美国，超过200亿美元，如果美国每个MS患者仅用一种修改药物治疗，更不用说生产率失去的额外费用和其他医疗保健。 MS的原因仍然未知。人们普遍认为遗传的组合环境因素决定了疾病的敏感性。维生素D缺乏症正在出现 MS的重要环境风险。尚不知道的是生命早期维生素D缺乏如何影响对MS的敏感性。先前的研究表明，MS患者的血清维生素D水平较高与复发风险较低有关，与其免疫调节功能一致。但是，这个维生素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作。一个高维生素D饮食减轻小胶质细胞的激活并减少脱髓鞘，提示神经保护作用维生素D.白介素-34（IL-34）的作用最近已被证明是至关重要的小胶质细胞。 IL-34由CNS中的神经元产生，其表达在产后时达到峰值然后，成年中的发展和维生素D会下降，可以积极调节IL-34表达。在一起， IL-34的表达时序/模式和功能使其成为维生素D介导的主要候选者神经保护分子，最终可能导致MS易感性降低。长期目标这项研究是了解早期生命中足够的维生素D的机制反对MS的发展。拟议项目的总体目的是使用转基因小鼠 - 神经元特异性诱导型维生素D受体基因敲除小鼠，以阐明维生素D信号在上早期生活中的神经元改变了小胶质细胞表型。我们的主要假设是维生素D小胶质细胞通过增强神经元中IL-34和/或其他因素的产生进入神经保护表型在开发中枢神经系统中。这项研究基础的理由是，一旦早期生命维生素D的相关性缺乏症和MS易感性已完全定义，这将是制定公共卫生政策的基础操纵MS易于修改的风险因素。目的是：1）阐明IL-34在维生素D介导的神经保护作用，2）确定维生素D是否调节IL-34和炎症细胞因子早期生命感染期间中枢神经系统的反应，以及3）确定早期维生素D的不足是否不足增强对MS动物模型EAE的敏感性。这些结果将具有重要的积极影响是因为它们将定义早期维生素D介导的神经保护的细胞机制。了解这种环境因素如何影响MS风险将是迈向最终的重要一步目标 - 防止MS。