Indiana University-Purdue University Indianapolis (IUPUI) / Heritable disorders of phosphate handling are the most common cause of hypophosphatemic rickets in developed countries. Isolated renal phosphate wasting and subsequent low serum phosphate concentrations may result from a number of genetic disorders that include: autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), and autosomal recessive hypophosphatemic rickets (ARHR). Fibroblast growth factor-23 (FGF23), identified as the causative gene in ADHR, is produced in bone and plays a central role in kidney phosphate regulation. Increased serum concentrations of FGF23 lead to renal phosphate wasting through down regulation of renal sodium-phosphate co-transporters. However, the molecular mechanisms of FGF23 bioactivity in hormonal phosphate regulation are largely unknown.
An experimental focus of this dissertation was to investigate the molecular mechanisms of FGF23-mediated phosphate regulation in the bone-kidney hormonal axis. To this end, the role of Dentin Matrix Protein 1 (DMP1), newly identified as the gene responsible for ARHR, was further defined by the identification of a novel large deletion as well as testing the molecular consequences of DMP1 mutations.
FGF23 requires a signaling complex composed of Klotho and an FGFR for bioactivity, however, the location and composition of the signaling complex is unknown. Klotho localizes to the renal distal convoluted tubule, whereas the sodium phosphate co-transporters are expressed within the renal proximal tubules. The molecular mechanisms of FGF23 signaling were investigated by isolating a novel marker of FGF23 bioactivity using array technology, determining the location of initial FGF23 signaling in the kidney, and by identifying a novel mutation in a receptor upstream of FGF23 production. Taken together, these results increase the knowledge of the molecular mechanisms of phosphate homeostasis in relation to FGF23 bioactivity, leading to the identification of potentially novel therapeutic targets. / indefinitely
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/1890 |
| Date | 23 June 2009 |
| Creators | Farrow, Emily |
| Contributors | White, Kenneth |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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