FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS

Project: Research project

Description

DESCRIPTION (provided by applicant): The regulation of serum phosphate concentrations is a complex process and our current models are far from complete. We positionally cloned a novel gene from chromosome 12p13.3, FGF23, that encodes a secreted factor, and demonstrated that, when mutated, the gene is responsible for the renal phosphate wasting disorder autosomal dominant hypophosphatemic rickets (ADHR). We also determined that FGF-23 is overexpressed in tumors causing oncogenic hypophosphatemic osteomalacia (OHO), and in vivo evidence supports the role of FGF-23 as a phosphaturic substance. The cellular and molecular mechanisms by which FGF-23 causes isolated renal phosphate wasting are currently unknown, however. The long-term goals of the present studies are to understand the molecular physiology and function of genes involved in regulating renal phosphate reabsorption controlled by FGF-23. The study of the phosphate-wasting metabolic syndromes, ADHR and OHO, provides a unique opportunity to discover novel pathways controlling renal phosphate homeostasis. Currently there are no animal models for ADHR, thus limiting the ability to test hypotheses regarding the physiological mechanisms underlying the disease. The hypothesis to be tested within this proposal is: FGF-23 acts through a specific receptor to cause changes in gene transcription and translation in kidney proximal tubule that result in decreased renal absorption of phosphorous. We will test this hypothesis through the following Specific Aims: (1) to test for changes in the expression of renal and skeletal genes in mice that may be regulated by FGF-23 in vivo; (2) to determine the FGF receptor(s) involved in FGF-23 actions on the kidney proximal tubule; and (3) to develop an appropriate mouse model of ADHR and to understand the manifestations of the disorder. The results of the proposed studies will provide insight into the pathogenesis of ADHR and OHO, as well as lead to improved understanding of the mechanisms dictating phosphate homeostasis in the long-term.
StatusFinished
Effective start/end date12/27/023/31/16

Funding

  • National Institutes of Health: $321,494.00
  • National Institutes of Health: $231,770.00
  • National Institutes of Health: $339,300.00
  • National Institutes of Health: $231,770.00
  • National Institutes of Health: $219,760.00
  • National Institutes of Health: $231,770.00
  • National Institutes of Health: $338,575.00
  • National Institutes of Health: $314,489.00
  • National Institutes of Health: $317,666.00
  • National Institutes of Health: $327,425.00
  • National Institutes of Health: $49,999.00
  • National Institutes of Health: $226,323.00
  • National Institutes of Health: $339,300.00
  • National Institutes of Health: $320,875.00

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Homeostasis
Phosphates
Kidney
Proximal Kidney Tubule
Genes
Iron
Autosomal Dominant Hypophosphatemic Rickets
Calcinosis
Serum
fibroblast growth factor 23
Osteomalacia
Rickets
Wasting Syndrome
Messenger RNA
Fibroblast Growth Factor Receptors
Mutation
Minerals
Organism Cloning
Protein Isoforms

ASJC

  • Medicine(all)