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（由申请人提供）：在过去的十年里，维生素D的研究有了显著的复兴。有两个关键概念支撑了人们对维生素D的健康益处的重新关注。首先是关于全球普遍存在的维生素D不足的持续争论，以及如何通过常规的阳光照射和饮食摄入来安全地达到最佳的维生素D水平。其次，除了对骨骼的传统作用外，维生素D还可能促进健康益处。根据最近的一项数据审查，医学研究所（IOM）发表了一些声明，旨在解决有关维生素D和人类健康的新观点的一些关键问题。根据骨骼对维生素D的反应，提高了所有年龄组的维生素D推荐膳食摄取量。然而，IOM的报告也认识到需要进一步的研究来更好地定义维生素D的“非经典”健康益处。这些建议的长期影响关键取决于一个问题——如何定义维生素D充足和不足？拟议的项目描述了量化最佳维生素D及其与人体健康的关系的新范式。总体目标是证明维生素D活性不是简单地由25-羟基维生素D （25D）的血清总水平决定的，而是取决于这种代谢物对靶细胞的生物利用度，以及它随后通过酶1¿-羟化酶（CYP27B1）转化为活性的1,25-二羟基维生素D （1,25D）。该建议假设25D进入靶细胞的能力受到其与血清维生素D结合蛋白（DBP）的关联的影响，“游离”而不是“DBP结合”的25D是这种代谢物的生物活性形式。该提案的总体目标是通过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探讨DBP浓度和维生素D代谢物结合亲和力的变化如何影响维生素D充足和缺乏条件下这些小鼠对25D和1,25d的反应。这些实验的数据随后将与人类研究相关，其中DBP浓度和结合亲和力受到DBP基因遗传变异的强烈影响。人体研究将包括在大量患者队列中分析舒张压和游离25D/ 1,25d，并对维生素D功能进行多种测量，但也将涉及利用亲本维生素D或25D进行补充的试点研究。这些分析将采用一种新的数学算法来测定血清游离25D和1,25 d，并将使用新的测定技术来物理测量血清游离25D水平。该模型不仅提出了定义最佳维生素D状态的新范式，而且旨在强调维生素D健康的更“个性化”视角，将维生素D的经典和非经典作用结合起来。