DBP and the bioavailability and function of vitamin D

描述(申请人提供)：在过去的十年里，维生素D的研究出现了显著的复兴。两个关键概念支撑了人们对维生素D对健康益处的新兴趣。首先是关于维生素D缺乏在全球范围内普遍存在的持续辩论，以及如何通过传统的阳光照射和饮食摄入安全地实现最佳的维生素D状态。其次，除了对骨骼的传统影响外，维生素D还具有促进健康的潜力。在最近的一次数据审查之后，医学研究所(IOM)发表了旨在解决一些关键问题的声明，这些问题涉及我们对维生素D和人类健康的新观点。根据骨骼对维生素D的反应，所有年龄组的推荐维生素D摄入量都有所提高。然而，国际移民组织的报告也认识到，有必要进行进一步研究，以更好地界定维生素D的非经典健康益处。这些建议的长期影响主要取决于一个问题--如何定义维生素D充足和不足？拟议的项目描述了一种量化最佳维生素D及其与人类健康关系的新范式。总的目的是证明维生素D的活性不是简单地由25-羟基维生素D(25D)的血清总水平来定义的，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�-羟基酶(CYP27B1)转化为活性的1，25-二羟基维生素D(1，25D)。该提议假设，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，25D是这种代谢物的生物活性形式。该提案的总体目标将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调查在维生素D充足和缺乏的条件下，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。这些实验的数据将与人类研究有关，在人类研究中，DBP浓度和结合亲和力受到DBP基因遗传变异的强烈影响。人体研究将包括对具有多种维生素D功能的大型患者队列中的DBP和FREE 25D/1，25D的分析，但也将包括一项利用父母维生素D或25D的试验性补充研究。这些分析将采用一种新的数学算法来确定血清游离25D和1，25D，并将使用新的检测技术来物理测量血清中游离25D的水平。该模型不仅提出了定义最佳维生素D状态的新范式，而且旨在突出对维生素D健康的更“个性化”的观点，包括维生素D的经典和非经典作用。

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. .