The effect of vitamin D3 on markers of oxidative stress in boys with X-linked ALD

 描述(由申请人提供)：在这份以患者为导向的职业发展指导奖的申请中，候选人寻求5年的工资和研究支持，以获得进一步的培训，并确定维生素D3对患有X连锁肾上腺脑白质营养不良(ALD；发病率1：17,000)的男孩氧化应激标志物的影响。ALD是一种遗传性发作性疾病，以脂肪酸堆积和随后的氧化应激为特征。40%的ALD男孩在他们生命的第一个十年患上炎症性脑脱髓鞘(CerALD)。不幸的是，我们没有办法确定有CEALD风险的男孩，也没有任何方法预防脑性ALD的发病。这些限制代表着我们对这些患者的护理标准存在巨大差距。为了解决这些限制，候选人和他的合作者考虑了CEALD当前知识的几个关键领域的关系：(1)ALD是由过氧体基因缺陷引起的，该缺陷导致脂肪酸积聚，使细胞暴露在脂质过氧化和其他氧化应激介质之下，(2)单核细胞系细胞主导脱髓鞘病变的前沿，(3)病变与多发性硬化症病变具有相同的组织学特征，后者已被认为与维生素D不足有关。有了这一知识，候选人已经生成了初步数据，显示(1)低血清25-OH维生素D水平可以预测cerALD的发生；(2)与对照组相比，ALD男性单核细胞和脑髓鞘细胞的谷胱甘肽水平较低；(3)ALD男孩脑脊液中的细胞因子表达谱与单核细胞系细胞中的氧化应激状态一致；最后，在自身免疫脱髓鞘的小鼠模型中，口服维生素D3可显著降低临床疾病，增加单核细胞内的谷胱甘肽水平。候选人提出了一项试点试验，以研究口服维生素D3对20名尚未发展为脑性ALD的ALD男孩的血液和大脑氧化应激生物标记物的影响。在目标1中，候选人将使用核磁共振技术来监测氧化应激和炎症的大脑生物标记物，以应对维生素D水平的上升。在目标2中，候选人将使用12色流式细胞术和串联质谱仪来研究口服维生素D3对研究参与者特定免疫细胞亚群中氧化应激标志物的影响。在目标3中，候选人 将使用生物库ALD单核细胞来定义将维生素D暴露与谷胱甘肽和细胞因子调节联系起来的代谢和免疫学途径。这位候选人的长期目标是开发预防脑部ALD的治疗方法和生物标记物。在美国越来越多的州，将ALD添加到通用新生儿筛查小组中，增强了该项目的紧迫性。

 DESCRIPTION (provided by applicant): In this application for a Mentored Patient-Oriented Career Development Award, the candidate seeks 5 years of salary and research support to obtain further training and define the effect of vitamin D3 on markers of oxidative stress in boys with X-linked adrenoleukodystrophy (ALD; incidence 1:17,000). ALD is an inherited paroxysmal disease characterized by fatty acid accumulation and subsequent oxidative stress. Forty percent of ALD boys develop inflammatory cerebral demyelination (cerALD) in their first decade of life. Unfortunately, we have no means of identifying boys at risk for cerALD nor do we have any means of preventing the onset of cerebral ALD. These limitations represent enormous gaps in our standard of care for these patients. To address these limitations, the candidate and his collaborators consider the relationship of several key areas of current knowledge in cerALD: (1) ALD results from a peroxisomal gene defect that causes an accumulation of fatty acids which expose cells to lipid peroxides and other mediators of oxidative stress, (2) monocyte-lineage cells dominate the leading edge of the demyelinating lesions and (3) the lesions shares histologic features with multiple sclerosis lesions, a disease that has been linked to vitamin D insufficiency. Armed with this knowledge, the candidate has generated preliminary data showing that (1) low serum 25-OH vitamin D levels predict the onset of cerALD; (2) monocytes and brain myelin in ALD males have low glutathione levels compared to controls; (3) the spinal fluid from cerebral ALD boys shows a cytokine expression profile consistent with oxidative stress in monocyte-lineage cells; and lastly, (4) that oral vitamin D3 supplementation in a murine model of autoimmune demyelination significantly reduces clinical disease and increases intracellular glutathione levels in monocytes. The candidate proposes a pilot trial to study the effect of oral vitamin D3 supplementation on blood and brain biomarkers of oxidative stress in 20 ALD boys who have not yet developed cerebral ALD. In Aim 1 the candidate will use MRI techniques to monitor brain biomarkers of oxidative stress and inflammation in response to rising vitamin D levels. In Aim 2, the candidate will use 12-color flow cytometry and tandem mass spectrometry to study the effect of oral vitamin D3 supplementation on markers of oxidative stress in the specific immune cell subsets of study participants. In Aim 3, the candidate will use bio banked ALD monocytes to define the metabolic and immunologic pathways linking vitamin D exposure with glutathione and cytokine modulation. The candidate's long term goal is to develop treatments and biomarkers for the prevention of cerebral ALD. The addition of ALD to universal newborn screening panels in an increasing number of US states bolsters the project's immediate relevance.