DBP and the bioavailability and function of vitamin D

DBP 与维生素 D 的生物利用度和功能

基本信息

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
项目类别：
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

项目摘要

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）：在过去的十年中，维生素 D 研究出现了显着的复兴，两个关键概念支撑了人们对维生素 D 的健康益处的新兴趣。首先是关于维生素 D 在全球范围内的流行程度的持续争论。 D 不足，以及如何通过传统的阳光照射和饮食摄入来安全地达到最佳的维生素 D 状态。根据最近的数据审查，维生素 D 具有促进健康益处的潜力。医学的(IOM) 发表声明，旨在解决有关维生素 D 和人类健康新观点的一些关键问题，根据骨骼对维生素 D 的反应，提高了所有年龄段维生素 D 的推荐膳食摄入量。报告还认识到需要进一步研究，以更好地定义维生素 D 的“非经典”健康益处。这些建议的长期影响很大程度上取决于一个问题：如何定义维生素 D 充足和不足？项目描述量化最佳维生素 D 及其与人类健康关系的新范例，总体目标是证明维生素 D 活性并非简单地由 25-羟基维生素 D (25D) 的血清总水平定义，而是取决于该代谢物的生物利用度。到达靶细胞并随后通过酶 1¿ 转化为活性 1,25-二羟基维生素 D (1,25D)该提案开创了 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，其中“游离”而不是“DBP 结合”25D 是生物活性形式。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。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在维生素 D 充足和缺乏的条件下对 25D 和 1,25D 的反应，然后将这些实验的数据与人类研究相关。其中 DBP 和结合亲和力受 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纳入 DBP 和游离 25D/1,25D 的浓度，并进行维生素 D 功能的多种测量。还涉及利用亲本维生素 D 或 25D 进行的试点补充研究。这些分析将采用新的数学算法来确定血清游离 25D 和 1,25D，并将使用新的测定技术来物理测量游离 25D 的血清水平。提出了定义最佳维生素 D 状态的新范式，但也旨在强调维生素 D 健康的更加“个性化”的观点，其中将结合维生素 D 的经典和非经典作用。