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The primary role of 1,25(OH)₂D and the vitamin D receptor (VDR) during growth is to mediate intestinal calcium (Ca) absorption by regulating the expression of genes (e.g., Trpv6, S100g) that control Ca fluxes through enterocyte. In contrast to the well-defined role during rapid growth, the understanding of 1,25(OH)₂D signaling in post-growth, mature adult or the elderly is poor. Some observational studies suggest intestinal 1,25(OH)₂D signaling is not important to Ca absorption and bone for mature adult. In the elderly, intestine develops resistance to 1,25(OH)₂D action which might be due to age-related reductions in intestinal VDR level. In addition, there is lack of evidence that directly tests the role of 1,25(OH)₂D action in the distal intestine post-growth. My dissertation research focuses on discovering the importance of 1,25(OH)₂D signaling from both the temporal and spatial perspectives. By using 4-month old, whole intestine or large intestine VDR knockout mice, we found that for mature mice, 1,25(OH)₂D signaling plays a minimal role in regulating Ca absorption and protecting bone mass when dietary Ca intake is adequate. In contrast, 1,25(OH)₂D signaling in the whole intestine, and to a lesser extent the proximal colon, is critical to upregulate Ca absorption and protect bone when dietary Ca intake is low. Next, we proved that the Ca absorptive machinery in the proximal colon can be locally stimulated to enhance the expression of Trpv6 by 1,25(OH)₂D released from glycoside and glucuronide forms of calcitriol. Furthermore, our transcriptomic analysis on 1,25(OH)₂D-regulated genes in the duodenum of mature (4-month old), middle-aged (11.5-month old), and old (20.5-month old) mice suggest although aging did reduce the induction of some genes by 1,25(OH)₂D, this effect is not universally present across the genome and it is not related to intestinal Vdr expression. The findings from my dissertation research serve as a foundation for future research to identify a) the potential of specifically targeting proximal colon to increase intestinal Ca absorption and protect bone in adult; b) the molecular mechanisms that contribute to the aging-associated, non-universal resistance to 1,25(OH)₂D action.

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Although maternal vitamin D status has been linked to asthma in offspring, the relationship between vitamin D status and asthma in adults still remains unclear. The current study assessed the relationship between measures of vitamin D status and self-reported asthma/wheeze in 186 healthy women aged 18-30 years. Although the risk of asthma/wheeze symptoms was three-times higher among women with low dietary vitamin D intake (<200 IU>/day) than in those with higher vitamin D intake, suboptimal serum levels of 25(OH)D ( <70 nmol>/L) were associated with a 48% lower risk of asthma/wheeze than “optimal” serum levels. These contradictory effects underscore the poor correlation between dietary vitamin D intake and serum vitamin levels and suggest that other components in vitamin D-rich foods may be protective. Alternatively, women with higher serum vitamin D levels may have spent more time outdoors, increasing their exposure to asthma triggers. This study also identified predictors of serum 25 (OH) D in this sample. In addition to total dietary vitamin D (r= 0.2; p=0.03), intake of cold cereal (p=0.02) also significantly predicted serum 25(OH)D levels. Among non-dietary factors, month of blood draw (p=0.05) and oral contraceptive use (p<0.0001) were positive predictors of serum 25(OH) D; sunscreen use (p=0.04) was a negative predictor. After adjusting for covariates, oral contraceptive use was associated with 25(OH)D levels that were on average 24 nmol/L greater than those observed in women who did not use oral contraceptives. Additional prospective studies are needed to further evaluate the relationship between vitamin D status and asthma.

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In der vorliegenden Studie wurde der Zusammenhang des depressiven Syndroms mit dem Vitamin D-Spiegel an einer Stichprobe gerontopsychiatrischer Patienten (n = 140) der Neurogerontopsychiatrischen Tagesklinik Würzburg untersucht. Die Depressivität der Patienten zu Beginn und im Verlauf der Behandlung wurde zum einen mittels der ICD-10-Klassifikation, zum anderen mittels des Scores auf der GDS- und Hamilton-Skala zu Beginn und Ende des Aufenthalts in der Tagesklinik sowie bei einer poststationären Kontrolle bestimmt. Der Vitamin D-Spiegel wurde bei Behandlungsbeginn bestimmt und im Falle eines Mangels 1000 IU Vitamin D am Tag oral substituiert. Hierbei zeigte sich kein Zusammenhang zwischen der Ausprägung des depressiven Syndroms und dem Vitamin D-Spiegel zu Beginn der Behandlung. Dagegen stellte sich heraus, dass Patienten mit einem höheren Spiegel eine deutlichere Verbesserung der depressiven Symptome auf der GDS im Verlauf der Behandlung erfuhren. Außerdem bestand eine signifikante negative Korrelation zwischen BMI und Vitamin D-Spiegel sowie eine Abhängigkeit der Spiegelhöhe von der Jahreszeit. Vitamin D könnte nach den Ergebnissen dieser Studie möglicherweise eine wirkungssteigernde und nebenwirkungsarme Komedikation in der antidepressiven Therapie von älteren psychisch erkrankten Menschen darstellen. Es bedarf weiterer ausführlicher Forschung über den neurophysiologischen Zusammenhang zwischen Vitamin D und der Schwere einer depressiven Erkrankung. Besonders hinsichtlich der Verwendung von Vitamin D als Komedikation gilt es, weitere intensive Forschung in Form von gut designten, randomisierten Fall-Kontroll-Studien und prospektiven Interventionsstudien zu betreiben, um die Therapie von depressiven Patienten im höheren Lebensalter weiter zu verbessern. / Depression is a common psychiatric disorder among geriatric patients that decreases the quality of life and increases morbidity and mortality. Vitamin D as a neurosteroid hormone might play a role in the onset and treatment of depression. In the present study the association between depressive symptoms and vitamin D concentration in serum was evaluated. 140 patients of a psychogeriatric day-care unit were included. The geriatric depression score (GDS) and the Hamilton depression rating scale (HDRS) were assessed at the beginning and end of treatment, GDS-scores additionally 6 weeks after discharge from the day-care unit. Vitamin D levels were measured at the beginning of the treatment. Patients with levels below 30 mg/l were treated with 1000 IU Vitamin D per day. There was no association between the severity of depression symptoms and the concentration of vitamin D at the beginning of the treatment. Patients with higher vitamin D levels showed a stronger decline of depressive symptoms measured by the GDS during their stay in the day-care unit. Although no association between vitamin D concentration and severity of depression symptoms was found, vitamin D substitution could improve the effectiveness of an antidepressive treatment in geriatric patients. Further investigation is needed to evaluate the neurophysiological association between the serum concentration of vitamin D and symptoms of depression.

Traumatic brain injuries (TBI) are a leading cause of death worldwide. Previous research supports a relationship between vitamin D and TBI outcomes; however, they rely on animal studies. This review aimed to examine the neuroprotective role of vitamin D in humans with TBIs. A search was completed (PubMed and Scopus) following PRISMA guidelines to review publications investigating the relationship between vitamin D deficiency (VDD) and TBI or the effect of vitamin D supplementation on TBI outcomes; 8 studies were identified. Patients had thefollowing ranges: 26-88% deficiency and 62-88% insufficiency compared to 24% and 49% of the general population. Supplementation reduced ventilation duration, improved the quality of consciousness, and significantly improved mini-mental status examination scores. Research showed high percentages VDD/insufficiency in TBI patients. Results remain consistent suggesting a neuroprotective effect of vitamin D. Further research is needed to understand the effect of vitamin D status and supplementation on TBIs.

Alteration in diet and knockdown of detoxification genes impacts the response of C. elegans to oxygen deprivation stress. I hypothesized that feeding worms a vitamin D3-supplementation diet would result in differential oxygen deprivation stress response. We used a combination of wet lab and transcriptomics approach to investigate the effect of a vitamin-D3 supplemented diet on the global gene expression changes and the anoxia response phenotype of C. elegans (Chapter 2). C. elegans genome consists of 143 detoxification genes (cyp and ugt). The presence of a significant number of genes in these detoxification families was a challenge with identifying and selecting specific cyp and ugt genes for detailed analysis. Our goal was to understand the evolution, phylogenetic, and expression of the detoxification enzymes CYPs and UGTs in C. elegans (Chapter 3). We undertook a phylogenetic and bioinformatics approach to analyze the C. elegans, detoxification family. Phylogenetic analysis provided insight into the association of the human and C. elegans xenobiotic/endobiotic detoxification system. Protein coding genes in C. elegans have been predicted to be human orthologs. The results of this work demonstrate the role of C. elegans in the identification and characterization of vitamin D3 induced alterations in gene expression profile and anoxia response phenotypes and the identification of human orthologs for the detoxification enzymes and provides insight into the gene expression pattern.

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