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

维生素 D3 对 X 连锁 ALD 男孩氧化应激标志物的影响

基本信息

批准号：
9293400
负责人：
Keith Van Haren
金额：
$ 18.58万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293400
关键词：
Address Adrenal Glands Adrenoleukodystrophy Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Area Autoimmune Process Biological Biological Markers Blood Brain CCL2 gene Caring Catabolism Cell Lineage Cells Cerebrospinal Fluid Cerebrum Child Cholecalciferol Clinical Clinical Research Clinical Trials Clinical/Radiologic Color Complication Data Defect Demyelinating Diseases Demyelinations Disease Dose Drug Kinetics Encephalitis Enrollment Fatty Acids Flow Cytometry Free Radicals Future Gadolinium Genes Geographic state Glutathione Goals Grant Hereditary Disease Histologic Human IL8 gene Immune Immunologic Markers Immunologics Incidence Individual Inflammation Inflammatory Inherited Injury Interleukin-1 beta K-Series Research Career Programs Knowledge Lead Lesion Leukocytes Life Link Lipid Peroxidation Lipid Peroxides Lipid-Laden Macrophage Lipids Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Mass Spectrum Analysis Measures Mediator of activation protein Mentors Metabolic Metabolism Methods Molecular Profiling Monitor Multiple Sclerosis Multiple Sclerosis Lesions Myelin NADH NADP Neonatal Screening Neurodegenerative Disorders Neurologist Oral Outcome Oxidation-Reduction Oxidative Stress Oxidoreductase Participant Pathogenesis Pathologic Pathway interactions Patient Care Patients Phenotype Positioning Attribute Prevention Preventive therapy Production Proteins Research Methodology Research Support Risk Role Safety Serum Severity of illness Small Interfering RNA Supplementation Techniques Tissues Training Very Long Chain Fatty Acid Vitamin D Vitamin D supplementation Wages Woman Work aged biobank boys brain tissue cytokine falls high risk in vivo insight interest macrophage male men monocyte mouse model multiple sclerosis patient neuroimmunology neuroinflammation patient oriented phase III trial pilot trial prevent public health relevance response standard of care tandem mass spectrometry

项目摘要

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.

描述（由申请人提供）：在这份申请中，申请人寻求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X连锁肾上腺脑白质营养不良（ALD;发病率1：17，000）男孩氧化应激标志物的影响。ALD是一种以脂肪酸积累和随后的氧化应激为特征的遗传性阵发性疾病。40%的ALD男孩在他们生命的第一个十年中发生炎性脑脱髓鞘（cerALD）。不幸的是，我们没有办法识别有cerALD风险的男孩，也没有任何方法预防脑ALD的发作。这些局限性代表了我们对这些患者的护理标准存在巨大差距。为了解决这些局限性，候选人及其合作者考虑了cerALD当前知识的几个关键领域之间的关系：（1）ALD是由过氧化物酶体基因缺陷引起的，该基因缺陷导致脂肪酸的积累，脂肪酸的积累使细胞暴露于脂质过氧化物和其他氧化应激介质，（2）单核细胞系细胞支配脱髓鞘病变的前缘和（3）病变与多发性硬化病变具有相同的组织学特征，这种疾病与维生素D不足有关。有了这些知识，候选人已经产生了初步数据，表明（1）低血清25-OH维生素D水平预测cerALD的发作;（2）与对照组相比，ALD男性中的单核细胞和脑髓鞘具有低谷胱甘肽水平;（3）来自脑ALD男孩的脊髓液显示出与单核细胞谱系细胞中的氧化应激一致的细胞因子表达谱;最后，（4）在自身免疫性脱髓鞘的鼠模型中口服维生素D3补充剂显著减少临床疾病并增加单核细胞中的细胞内谷胱甘肽水平。候选人提出了一项试点试验，研究口服维生素D3补充剂对20名尚未发展为脑ALD的ALD男孩的血液和大脑氧化应激生物标志物的影响。在目标1中，候选人将使用MRI技术来监测大脑氧化应激和炎症的生物标志物，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法研究口服维生素D3补充剂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的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途径。候选人的长期目标是开发预防脑ALD的治疗方法和生物标志物。在越来越多的美国州，ALD被添加到新生儿筛查小组中，这增强了该项目的直接相关性。