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. .

Public Health Relevance

Vitamin D has been linked to a wide range of human health benefits, but the optimal level of vitamin D required for these effects is far from clear. We have hypothesized that rather than simply measuring total serum concentrations of vitamin D, it is more biologically and clinically relevant to determine free or bioactive levels of serum vitamin D metabolites. To demonstrate this, the proposed project will utilize in vivo mouse and human models in which free serum vitamin D is altered as a consequence of variable expression of the serum vitamin D binding protein, with the overall aim of the project being to present an entirely new paradigm for defining optimal vitamin D status in humans. .

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Jenkinson, Carl; Taylor, Angela E; Storbeck, Karl-Heinz et al. (2018) Data comparing the separation and elution of vitamin D metabolites on an ultra performance supercritical fluid chromatography tandem-mass spectrometer (UPSFC-MS/MS) compared to liquid chromatography (LC) and data presenting approaches to UPSFC method opti Data Brief 20:426-435
Muñoz Garcia, Amadeo; Kutmon, Martina; Eijssen, Lars et al. (2018) Pathway analysis of transcriptomic data shows immunometabolic effects of vitamin D. J Mol Endocrinol 60:95-108
Jeffery, Louisa E; Henley, Peter; Marium, Nefisa et al. (2018) Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. J Autoimmun 88:50-60
Schwartz, Janice B; Gallagher, J Christopher; Jorde, Rolf et al. (2018) Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations. J Clin Endocrinol Metab 103:3278-3288
Shieh, Albert; Ma, Christina; Chun, Rene F et al. (2018) Associations Between Change in Total and Free 25-Hydroxyvitamin D With 24,25-Dihydroxyvitamin D and Parathyroid Hormone. J Clin Endocrinol Metab 103:3368-3375
Tamblyn, J A; Jenkinson, C; Larner, D P et al. (2018) Serum and urine vitamin D metabolite analysis in early preeclampsia. Endocr Connect 7:199-210
Shieh, Albert; Ma, Christina; Chun, Rene F et al. (2017) Effects of Cholecalciferol vs Calcifediol on Total and Free 25-Hydroxyvitamin D and Parathyroid Hormone. J Clin Endocrinol Metab 102:1133-1140
Hassan-Smith, Zaki K; Jenkinson, Carl; Smith, David J et al. (2017) 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression. PLoS One 12:e0170665
Tamblyn, J A; Susarla, R; Jenkinson, C et al. (2017) Dysregulation of maternal and placental vitamin D metabolism in preeclampsia. Placenta 50:70-77
Nielson, Carrie M; Jones, Kerry S; Chun, Rene F et al. (2016) Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations. J Clin Endocrinol Metab 101:2226-34

Showing the most recent 10 out of 19 publications