This is a new application for a FIRST Award which proposes to study the regulation of EGF receptor expression in UMR rat osteoblast-like cells by PTH, calcitriol, and retinoic acid. Preliminary data indicates that PTH and calcitriol increase EGF binding and responses in UMR cells, and that this effect appears to be due to an increase in EGF receptor number rather than a change in binding affinity. Further analyses with Northern blot and RNase protection assays demonstrate that both agents induce an increase in steady state EGF receptor mRNA levels by 3 to 5-fold. Preliminary data using EGF receptor promoter constructs linked to a luciferase reporter gene demonstrate that these effects are likely transcriptional in nature. Retinoic acid alone also increased EGF binding, but blunted the effects of PTH and calcitriol on EGF binding. The hypotheses are that PTH, calcitriol, and retinoic acid all increase transcriptional rates of the EGF receptor, that retinoic acid interferes with PTH-stimulated cAMP production, and that retinoic acid modulates the effects of vitamin D on a putative VDRE in the 5' flanking region of the EGF receptor gene. The current proposal will explore in more detail the molecular basis of the effects of calciotropic hormones on EGF receptor expression.
The Specific Aims are: 1) to determine the mechanism for the increase in EGF receptor mRNA in response to PTH, calcitriol, and retinoic acid; 2) to identify the regions in the EGF receptor promoter which are responsible for the actions of PTH, calcitriol, and retinoic acid on transcription; 3) to define the mechanism of interaction of calcitriol with retinoic acid; and 4) to investigate the mechanism of interaction of retinoic acid and PTH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK051099-02
Application #
2518542
Study Section
General Medicine B Study Section (GMB)
Program Officer
Margolis, Ronald N
Project Start
1996-09-21
Project End
2001-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Disthabanchong, Sinee; Hassan, Hatim; McConkey, Charles L et al. (2004) Regulation of PTH1 receptor expression by uremic ultrafiltrate in UMR 106-01 osteoblast-like cells. Kidney Int 65:897-903
Gonzalez, E A; McConkey, C L; Martin, K J (2002) Mechanism of retinoic acid induced attenuation of PTH action in UMR 106-01 cells. Calcif Tissue Int 71:235-42
Disthabanchong, Sinee; Martin, Kevin J; McConkey, Charles L et al. (2002) Metabolic acidosis up-regulates PTH/PTHrP receptors in UMR 106-01 osteoblast-like cells. Kidney Int 62:1171-7
Gonzalez, Esther A; Disthabanchong, Sinee; Kowalewski, Rodney et al. (2002) Mechanisms of the regulation of EGF receptor gene expression by calcitriol and parathyroid hormone in UMR 106-01 cells. Kidney Int 61:1627-34
Gonzalez, Esther A; Lund, Richard J; Martin, Kevin J et al. (2002) Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7. Kidney Int 61:1322-31
Disthabanchong, S; Gonzalez, E A; Martin, K J (2002) Soluble IL-6 receptor levels in patients on chronic hemodialysis. Clin Nephrol 58:289-95
Disthabanchong, S; Gonzalez, E A (2001) Regulation of bone cell development and function: implication for renal osteodystrophy. J Investig Med 49:240-9
Gonzalez, E A (2000) The role of cytokines in skeletal remodelling: possible consequences for renal osteodystrophy. Nephrol Dial Transplant 15:945-50