# PATHOGENESIS OF VITAMIN D REFRACTORY DISEASES > **NIH NIH R01** · DUKE UNIVERSITY · 1993 · $370,562 ## Abstract The vitamin D resistant disorders include a varied group of none diseases refractory to treatment. At present, limited knowledge regarding the pathophysiology of many such disorders precludes effective therapy. X-linked hypophosphatemic rickets (XLH) is the prototypic hypophosphatemic vitamin D resistant disease, characterized by renal phosphate (Pi) wasting, aberrant regulation of vitamin D metabolism and defective bone mineralization. Although these abnormalities are representative of those exhibited by many of the hypophosphatemic vitamin D resistant diseases, defective regulation of vitamin D metabolism is a variable derangement. Indeed, similar variability is exhibited by the murine homologues of the human diseases, the hyp- and gy-mouse. Our proposed studies are designed to continue investigation of the pathophysiological and genetic abnormalities underlying XLH and to further improve the treatment for affected subjects. Studies in the murine homologues will be employed to gain further insight to the pathophysiological mechanism(s) operative in this disease. Employing renal cross-transplantation we will explore of the abnormal renal Pi transport in the various mutant mice is uniformly due to an hormonal/Metabolic aberration (as documented in hyp-mice) or variably due to an intrinsic derangement of renal tubular function. In addition, we will use a variety of approaches to investigate the relationship between abnormal renal Pi transport and aberrant regulation of 1,25(OH)2D production. In renal cross-transplantation studies of hyp- mice, we will assess renal Pi transport and assay 25(OH)D-1- hydroxylase in the resultant animal models to determine the linkage between these abnormalities. In contrast, employing cultures of cells from the S1, S2, and S3 segments of the proximal concolutes tubules from hyp- and gy- mice, we will determine if occurrence of the Pi transport defect at alternate loci or unique distribution of 25(OH)D-1-hydroxylase activity underlies the variable occurrence of normal vitamin D metabolism in the hypophosphatemic vitamin D resistant diseases. Studies in the hyp-mouse will also include efforts to identify and characterize the humoral factor apparently underlying the abnormal renal Pi transport in this animal model. In these investigations we will assess the biological characteristics of the Pi transport inhibitory activity present in serum from hyp-mice and explore the liver as the potential organ that synthesizes this humoral factor. Additionally, we will use standard techniques to isolate the protein factor from the serum and perform structural analysis. Efforts to elucidate the genetic abnormality in XLH will be directed at localizing and eventually cloning the gene responsible for this disease. These studies will include linkage analysis, physical mapping of the Xp22.1 region ad ultimately fine structure mapping techniques. Finally, evaluation of the therapeutic strategy for XLH will place emphasis on determining if... ## Key facts - **NIH application ID:** 3155495 - **Project number:** 5R01AR027032-14 - **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:** 1993 - **Award amount:** $370,562 - **Award type:** 5 - **Project period:** 1980-08-01 → 1996-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/3155495 ## Citation > US National Institutes of Health, RePORTER application 3155495, PATHOGENESIS OF VITAMIN D REFRACTORY DISEASES (5R01AR027032-14). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155495. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*