The experiments outlined in this proposal examine the interaction between 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)and polypeptide growth factors in both developing and mature kidney. The calciotropic hormone, 1,25-(OH)2D3, has been found to be a potent regulator of cell growth and differentiation. Besides containing the enzyme (1alpha-hydroxylase) responsible for the synthesis of 1,25-(OH)2D3, the kidney both produces and is a target for several polypeptide growth factors which have paracrine activity and are required for both fetal renal development and renal growth. In bone, 1,25-(OH)2D3 alters the expression of these growth factors. Growth factors, IGF I in particular, may themselves regulate the production of 1,25(OH)2D3. Studies outlined in this application address the following issues: 1) The effect of 1,25-(OH)2D3 on the expression of polypeptide growth factors and on subsequent development of the metanephros; 2) The ontogeny of the vitamin D receptor (VDR), which mediates the activity of 1,25-(OH)2D3, and of the renal 1alpha-hydroxylase. 3) The effect of polypeptide growth factors on the 1alpha-hydroxylase; 3) The role of 1,25(OH)2D3 in modulating compensatory renal hypertrophy following uninephrectomy; 4) The effects of IGF I on Pi handling and vitamin D metabolism will be studied in X-linked hypophosphatemic rickets using the murine model, the Hyp mouse. This disease is characterized by low renal tubular reabsorption of phosphate and an abnormal 1alpha-hydroxylase response to hypophosphatemia. IGF I stimulates renal tubular reabsorption of phosphate and increases 1alpha-hydroxylase activity in response to hypophosphatemia.
| Grieff, M; Whyte, M P; Thakker, R V et al. (1997) Sequence analysis of 139 kb in Xp22.1 containing spermine synthase and the 5' region of PEX. Genomics 44:227-31 |
| Grieff, M (1997) New insights into X-linked hypophosphatemia. Curr Opin Nephrol Hypertens 6:15-9 |
| Grieff, M; Mumm, S; Waeltz, P et al. (1997) Expression and cloning of the human X-linked hypophosphatemia gene cDNA. Biochem Biophys Res Commun 231:635-9 |
| Grieff, M; Zhong, M; Finch, J et al. (1996) Renal calcitriol synthesis and serum phosphorus in response to dietary phosphorus restriction and anabolic agents. Am J Kidney Dis 28:589-95 |
| Wu, S; Finch, J; Zhong, M et al. (1996) Expression of the renal 25-hydroxyvitamin D-24-hydroxylase gene: regulation by dietary phosphate. Am J Physiol 271:F203-8 |
