# PATHOGENESIS OF VITAMIN D REFRACTORY DISEASES

> **NIH NIH R01** · DUKE UNIVERSITY · 1988 · $194,294

## Abstract

Our proposed studies are designed to investigate the role of
abnormal vitamin D metabolism in the pathogenesis of X-linked
hypophosphatemic rickets (XLH) and the effectiveness and
complications of long-term calcitriol and phosphate therapy in
patients with this disease.  Abnormalities of vitamin D
metabolism will be examined in affected humans and in Hyp-mice,
the murine homologue of the disorder.  Investigations in mutant
mice will include efforts to further characterize the abnormality
of 1,25(OH)2D biosynthesis evident in these animals (and in
patients with XLH).  In addition, we will employ a variety of
approaches to explore if the aberrant regulation of 1,25(OH)2D
production is secondary to alterations of the hormonal/metabolic
milieu in the diseased animals.  Using renal transplantation (Hyp
to normal; normal to Hyp-mouse) and assay of 25(OH)D-1 and
24R-Hydroxylase activities in resultant isografts, we will explore
the linkage between the primary genetic error in XLH, abnormal
renal phosphate transport, and the aberrantly regulated enzyme
activity.  Further, employing measurements of enzyme
hydroxylase activities in non-renal tissues and in renal tubule
suspensions in vitro, we will establish whether the abnormality of
1,25(OH)2D production occurs in all enzyme bearing tissues and if
it is due to abnormal phosphate transport.  In humans we will
determine whether defective regulation of 1,25(OH)2D production
is similar to that in mutant mice.  Studies in the Hyp-mice will
also include efforts to investigate whether the bone
mineralization defect is a consequence of abnormal vitamin D
metabolism and hypophosphatemia or is due in part to an intrinsic
derangement of the osseous structure.  In these investigations we
will employ renal transplantations to determine if presence of the
bone lesion is invariably associated with the characteristic renal
dysfunction exhibited in Hyp-mice.  Evaluation of the therapeutic
strategy for XLH will place emphasis on determining the
spectrum of complications attendant upon long-term therapy and
the impact of these events on patient care.  In addition, we will
test alternative therapeutic strategies to that already developed
if complications are severely limiting.  Collectively, the planned
studies will provide new information regarding the regulation of
vitamin D metabolism.  In addition, important perspective
concerning the pathogenesis of X-linked hypophosphatemic rickets
(and related vitamin D resistant diseases) will be obtained and
effective low-risk therapeutic strategies for these disorders
defined.

## Key facts

- **NIH application ID:** 3155491
- **Project number:** 5R01AR027032-09
- **Recipient organization:** DUKE UNIVERSITY
- **SAM.gov UEI:** TP7EK8DZV6N5
- **Principal Investigator:** MARC KENNETH DREZNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $194,294
- **Award type:** 5
- **Project period:** 1980-08-01 → 1992-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155491

## Citation

> US National Institutes of Health, RePORTER application 3155491, PATHOGENESIS OF VITAMIN D REFRACTORY DISEASES (5R01AR027032-09). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155491. Licensed CC0.

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