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Past Grant Recipients Nine CeDAR grants were awarded during 2006 to 2008. The recipients of these seed grants are listed below by year. ----------------------------------------------------------------------------------------------------------------- The two grant recipients for 2008 are listed below: Adit A. Ginde, MD, MPH University of Colorado Denver School of Medicine, Aurora, Colorado Vitamin D Deficiency and Chronic, Nonspecific, Musculoskeletal Pain [abstract pending]
Alan C. Rigby, PhD Beth Israel Deaconess Medical Center, Boston, Massachusetts In silico Discovery of Novel Vitamin-D Analogues [abstract pending]
----------------------------------------------------------------------------------------------------------------- The three grant recipients for 2007 are listed below: T. Alp Ikizler, MD Vanderbilt University Medical Center, Nashville, Tennessee Vitamin D, Insulin Resistance, and Inflammation in ESRD The pleiotropic effects of 1,25-Dihydroxyvitamin D 3 (VitD 3) and its synthetic analogs are now developing as an important area of research and these drugs are being increasingly recognized for their potent antiproliferative, pro-differentiative and immunomodulating activities. The broad goal of this grant application is to understand the mechanisms by which Vitamin D receptor activation leads to changes in insulin signaling in advanced uremia. We hypothesize that VitD 3 deficiency due to advanced chronic kidney disease leads to insulin resistance and that administration of a VitD 3 analog will restore insulin sensitivity in end-stage renal disease (ESRD) patients. We will test this hypothesis by the following specific aims through a prospective, controlled, randomized study: 1) To determine the effects of VitD 3 deficiency on insulin sensitivity ( as measured by hyperinsulinemic euglycemic clamp) and insulin signaling in non-diabetic ESRD patients 2 ) To determine the effects of VitD 3 administration/replacement on: a. insulin sensitivity ; b. insulin signaling; c. chronic inflammation. The data that will be obtained from the proposed studies will provide novel information on the etiology of insulin resistance and VitD 3 deficiency and will likely open up new avenues for further research on this area.
Robert Sidbury, MD Children’s Hospital Boston, Massachusetts Vitamin D Supplementation in Childhood Atopic Dermatitis: A Randomized Trial The role of vitamin D in atopic dermatitis (AD) is unknown. Clinically, most patients with AD suffer wintertime exacerbation and improve with exposure to sunlight. Though this phenomenon has historically been attributed to changes in ambient humidity, recent work identifying mutations in the epidermal envelope protein fillagrin has focused attention on the role of the skin barrier. Epidermal synthesis of vitamin D could have profound relevance because calcitriol regulates important cellular functions in keratinocytes and immunocompetent cells, which in turn mediate both anti-proliferative and pro-differentiating effects. This forms the therapeutic basis for calcitriol and vitamin D analog use in psoriasis vulgaris. Vitamin D-mediated innate immune responses also have been linked to human susceptibility to bacterial infections, and AD patients demonstrate increased susceptibility to staphylococcal superinfection. These studies highlight the role played by vitamin D in cutaneous metabolism and suggest a biologically plausible connection to AD. Dr Carlos Camargo (co-PI) and I have designed a double-blind, placebo-controlled, randomized trial to determine the role of oral vitamin D supplementation in patients with winter-onset or winter-exacerbated AD.
Marcello Tonelli, MD, SM University of Alberta, Edmonton (Canada) Vitamin D Status as a Determinant of Mortality in Remote-dwelling Canadian Dialysis Patients As yet unpublished work from our group indicates a significant independent association between the risk of death and remote residence location in Alberta dialysis patients. We hypothesize that inadequate vitamin D status may contribute to the excess risk of death in this northern dwelling population. We hypothesize that deficiency of 25D and 1,25D will be highly prevalent in Alberta HD population and will increase with more northerly residence location. We further hypothesize that there will be substantial seasonality in these levels, meaning that studies which examine the link between vitamin D insufficiency and outcomes in this population will need to make multiple assays of 25D and 1,25D to accurately assess vitamin D status. In this study we will collect clinical information and blood specimens in baseline and in follow-up on a large incident cohort of HD patients in Alberta. We will test the two hypotheses above in a subset of these participants to reduce costs. We will use these data and materials in support of a subsequent grant application to another agency, which will allow us to measure vitamin D status in all cohort participants (using baseline specimens only or multiple measurements, based on the findings of the current study).
----------------------------------------------------------------------------------------------------------------- The four grant recipients for 2006 are listed below: Alex Brown, PhD Washington University At St. Louis, Missouri Vitamin D in the Parathyroid Glands The parathyroid glands have been shown to express 1 a -hydroxylase (1 a OHase) mRNA and protein suggesting the existence of an autocrine system for the control of PTH involving local conversion of circulating 25(OH)D 3 to the hormonal form, 1,25(OH) 2D 3. This hypothesis is consistent with the observation that the elevated PTH levels in vitamin D deficiency correlate negatively with 25(OH)D 3, but not with 1,25(OH) 2D 3, which is typically unchanged. However, a role for the parathyroid 1 a OHase in the control of PTH has not been demonstrated. To address this, we will 1) determine if the 1 a OHase is required for control of PTH by 25(OH)D 3 in parathyroid cell culture using inhibitors and silencing RNA, and 2) establish whether 25(OH)D 3 regulates PTH in vivo using 1 a OHase knockout mice. The results of these studies will define the potential role of local 1,25(OH) 2D 3 production in the control of PTH, suggest new approaches for the design of vitamin D analogs for the treatment of secondary hyperparathyroidism in renal patients, and emphasize the importance for proper vitamin D nutrition in the control of calcium metabolism.
Adriana Dusso, PhD Washington University At St. Louis, Missouri Loss of Proximal Tubule Cell Function and the Progression of Kidney Disease: Optimal Vitamin D Therapy for Prevention In kidney disease, the progressive deterioration of the capacity of renal proximal tubular cell 1-hydroxylase to bioactivate 25-hydroxyvitamin D (25D) to 1,25-dihydroxyvitamin D (1,25D, calcitriol), the hormonal form of vitamin D, is a key determinant of the severity of secondary hyperparathyroidism (SH). High serum PTH in turn causes the skeletal abnormalities known as renal osteodystrophy and cardiovascular disorders that markedly increase mortality rates in these patients. Interestingly, in patients with a GFR below 20 ml/min, serum calcitriol can be normalized by 25D supplementation, thus demonstrating that impaired uptake of 25D prevails over the reduction in 1-hydroxylase in determining net renal 1,25D production. Megalin is the protein responsible not only for the uptake of 25D bound to its carrier, but also for tubular protein reabsorption. Renal megalin expression, markedly reduced in experimental kidney disease, is induced by 1,25D. Based upon the ability of 19-nor D2, a less calcemic calcitriol analog, to correct proteinuria in early kidney disease, and our demonstration that 25D treatment of renal proximal tubular cells cannot substitute for 1,25D in inducing the expression of C/EBPß, a transcription factor responsible for the induction of 1-hydroxylase and vitamin D receptor (VDR) gene expression, we propose that combined therapy with 25D and 19-nor-1,25D2, rather than exclusive 25D therapy, is necessary to effectively correct renal megalin, 1-hydroxylase and VDR levels, thereby improving renal tubular cell capacity to produce and respond to calcitriol in controlling not only SH, but also proteinuria, the best predictor of the progression of renal lesions and cardiovascular complications. These studies will test the proposed hypothesis and identify the underlying mechanisms, in the rat model of kidney disease.
David G. Gardner, MD University of California, San Francisco Role of Vitamin D Receptor in Blocking Cardiac Hypertrophy Recent evidence suggests that vitamin D exerts palliative effects in the cardiovascular and renal systems. Our previous work showed that the liganded vitamin D receptor (VDR) possesses anti-hypertrophic activity in cultured neonatal rat cardiac myocytes. Furthermore, VDR -/- mice have been shown to have enlarged hearts with activation of the hypertrophic gene program, albeit in the setting of mild-to-moderate hypertension. In the present study, we propose to generate a cardiac-selective deletion of the VDR gene using a conventional Cre-Lox approach. We will use a combination of echocardiography, immunohistochemistry and gene expression analyses to determine whether loss of VDR activity, without accompanying blood pressure changes, is capable of activating or amplifying the hypertrophy either at baseline or following application of a hypertrophic stimulus, like chronic isoproterenol infusion.
Yan Chun Li, PhD University of Chicago, Illinois Exploring the Role of VDR in Atherogenesis by Genetic Approach The main goal of my grant proposal is to explore the role of the vitamin D receptor (VDR) in development of atherosclerosis. Increasing evidence from epidemiological and clinical studies has suggested a protective role of vitamin D in the homeostasis of the cardiovascular system, but the exact mechanism of the cardiovascular protection remains unknown. 1,25-dihydrxyvitamin D is a multi-functional endocrine hormone and is known to regulate inflammatory reaction, cell proliferation and the renin-angiotensin system. Based on these biological properties, we hypothesize that vitamin D may protect against atherogenesis. We will test this hypothesis by comparing the development of atherosclerosis between LDL receptor (LDLR) knockout mice and LDLR knockout mice that lack VDR. If the hypothesis is correct, we expect that the double knockout mice will develop more severe atherosclerosis. We expect that this study will provide direct experimental evidence with regard to the protective role of VDR in atherogenesis.
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