DBP and the bioavailability and function of vitamin D

DBP 与维生素 D 的生物利用度和功能

• 批准号: 8579492
• 负责人: John S Adams
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579492
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Address; Affect; Affinity; Alleles; Animal Model; Attention; Basic Science; Binding; Binding Proteins; Bioavailable; Biological; Biological Assay; Biological Availability; Cell physiology; Cells; Cholecalciferol; Clinical; Clinical Sciences; Collaborations; Data; Dietary intake; Disease; Endocrinology; Environment; Enzymes; Exposure to; Genes; Genetic Variation; Health; Health Benefit; Health Sciences; Hormones; Human; Immunological Models; Institute of Medicine (U.S.); Joints; Knock-out; Knockout Mice; Link; Measures; Mediating; Mind; Mixed Function Oxygenases; Modeling; Molecular Chaperones; Mus; Oregon; Outcome; Patients; Pennsylvania; Peripheral; Phenotype; Population; Prevalence; Protein Binding; Recommendation; Recommended Dietary Allowance; Renaissance; Reporting; Research; Research Personnel; Role; Sampling; Seminal; Serum; Site; Skeleton; Sunlight; Supplementation; Technology; Testing; Tissues; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; Universities; Variant; Vitamin D; Vitamin D-Binding Protein; Vitamin D2; age group; base; bone; clinically relevant; cohort; experience; human DNA; human subject; improved; in vivo; innovation; interest; mathematical algorithm; medical schools; mouse model; novel; protein expression; public health relevance; research study; response; skeletal

DESCRIPTION (provided by applicant): In the last ten years there has been a remarkable renaissance in vitamin D research. Two key concepts have underpinned this renewed interest in the health benefits of vitamin D. First is the continuing debate on the worldwide prevalence of vitamin D-insufficiency, and how optimal vitamin D status can be safely achieved through conventional exposure to sunlight and dietary intake. Second is the potential for vitamin D to promote health benefits beyond its classical effects on the skeleton. Following a recent data review, the Institute of Medicine (IOM) has issued statements aimed at addressing some of the key questions concerning our new perspective on vitamin D and human health. The Recommended Dietary Allowance of vitamin D for all age groups was elevated based on bone responses to vitamin D. However, the IOM report also recognized the need for further research to better define 'non-classical' health benefits of vitamin D. The long-term impact of these recommendations is crucially dependent on one question - how does one define vitamin D-sufficiency and -insufficiency? The proposed project describes a new paradigm for quantifying optimal vitamin D and its relation to human health. The overall aim is to demonstrate that vitamin D activity is not simply defined by total serum levels of 25-hydroxyvitamin D (25D) but instead depends on the bioavailability of this metabolite to target cells and its subsequent conversion to active 1,25-dihydroxyvitamin D (1,25D) via the enzyme 1¿-hydroxylase (CYP27B1). The proposal hypothesizes that the ability of 25D to access target cells is influenced by its association with the serum vitamin D binding protein (DBP), with 'free' rather than 'DBP-bound' 25D being the bioactive form of this metabolite. The overall objective of the proposal will be to investigate the impact of DBP on the bioactivity of 25D using both mouse and human models. Studies using transgenic, knockout, and humanized mice will investigate how variations in the concentration and vitamin D metabolite binding affinity of DBP affect the response of these mice to 25D and 1,25D under conditions of vitamin D-sufficiency and -deficiency. Data from these experiments will then be related to studies in humans, where DBP concentration and binding affinity are strongly influenced by genetic variations in the DBP gene. Human studies will incorporate analysis of DBP and free 25D/1,25D in a large patient cohort with multiple measures of vitamin D function, but will also involve a pilot supplementation study utilizing parental vitamin D or 25D. These analyses will employ a new mathematical algorithm for determining serum free 25D and 1,25D and will use novel assay technology to physically measure serum levels of free 25D. This model not only puts forward a new paradigm for defining optimal vitamin D status but also aims to highlight a more 'personalized' perspective on vitamin D health that will incorporate both classical and non-classical actions of vitamin D. .

描述（由适用提供）：在过去的十年中，维生素D研究进行了显着的文艺复兴。两个关键概念是对维生素D的健康益处的重新兴趣的基础。首先是关于维生素D不平等世界普遍存在的持续辩论，以及通过常规接触阳光和饮食摄入量，如何可以安全地实现最佳的维生素D状态。其次是维生素D的潜力，可以促进其对骨骼的经典影响超出其经典影响。在最近的数据审查之后，医学研究所（IOM）发表了旨在解决有关我们对维生素D和人类健康的新观点的关键问题的陈述。 The Recommended Dietary Allowance of vitamin D for all age groups was elevated based on bone responses to vitamin D. However, the IOM report also recognized the need for further research to better define 'non-classical' health benefits of vitamin D. The long-term impact of these recommendations is completely dependent on one question - how does one define vitamin D-sufficiency and -insufficiency?拟议的项目描述了一种新的范式，用于量化最佳维生素D及其与人类健康的关系。总体目的是证明，维生素D活性不仅是由25-羟基维生素D（25D）的总血清水平定义的，而是取决于该代谢物向靶细胞的生物利用度以及随后转化为主动1,25-二羟基羟基羟基智能素D（1,25D）通过Enzyme的活性。该提案假设25D访问靶细胞的能力受其与血清维生素D结合蛋白（DBP）的关联的影响，其“自由”而不是“ DBP结合” 25D是该代谢物的生物活性形式。该提案的总体目标是使用小鼠和人类模型研究DBP对25D生物活性的影响。使用转基因，基因敲除和人源化小鼠的研究将研究DBP浓度和维生素D代谢物结合亲和力的变化如何影响这些小鼠对25D和1,25D的反应，而维生素D缺乏症和缺乏症的条件下。然后，这些实验的数据将与人类的研究有关，在该研究中，DBP浓度和结合亲和力受到DBP基因遗传变异的强烈影响。人类研究将在大型患者队列中与DBP和25D/1,25D进行分析，并通过多次测量维生素D功能进行分析，但还涉及利用亲本维生素D或25D的试点补充研究。这些分析将采用一种新的数学算法来确定无血清25D和1,25D，并将使用新颖的测定技术来物理测量免费25D的血清水平。该模型不仅提出了定义最佳维生素D状态的新范式，而且还旨在强调对维生素D健康的更加“个性化”的观点，该观点将纳入维生素D的经典和非经典作用。