Growth hormone (GH) is essential for postnatal growth in animals. At the cellular level GH elicits its actions by initially binding to a cell surface protein termed the growth hormone receptor (GHR). A variety of factors influence the expression of the GHR; GHR is virtually undetectable in fetal tissues while its expression increases dramatically during postnatal life. The factors controlling the developmentally-regulated expression of the GHR are not known. I have identified a novel enhancer element in the promoter-regulatory region of the murine GH receptor gene which exhibits developmentally-regulated DNA-binding activity in liver. Furthermore, the functional activity of this enhancer element in transient transfection assays is also developmentally-regulated. I HYPOTHESIZE that the identified enhancer element with its cognate trans-acting factor(s) play a role in the developmentally-regulated expression of the GHR gene. This proposal seeks SPECIFICALLY to elucidate the molecular mechanisms controlling the developmentally-regulated expression of the GHR gene. The experimental strategy detailed in this proposal is designed to test the role of the identified enhancer element in the developmentally-regulated expression of the GHR gene by site-directed mutagenesis, transient transfection assays of fetal and adult hepatocytes using chimeric reporter gene constructs, and by mapping of the DNase I hypersensitivity sites in the 5' flanking region. Following a preliminary biochemical characterization of the DNA-binding protein(s), the identity of these trans-acting factor(s) will be ascertained by cloning the cDNA encoding the genes for these putative transcription factor(s). These studies will (a) delineate the molecular basis for alterations in expression of the GHR gene in disorders of growth such as genetic short stature, intra-uterine growth retardation and malnutrition, enabling (b)the design of novel diagnostic tools and more effective treatment strategies for these disorders of growth and development in the human.

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 #
5R29DK049845-04
Application #
2905757
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sato, Sheryl M
Project Start
1996-06-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
Lu, Chunxia; Kumar, P Anil; Sun, Jinhong et al. (2013) Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. J Biol Chem 288:15725-35
Kumar, P Anil; Brosius 3rd, Frank C; Menon, Ram K (2011) The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathy. Curr Diabetes Rev 7:50-5
Sun, Jinhong; Kumar, P Anil; Thimmarayappa, Jamuna et al. (2011) Esterase 1 is a novel transcriptional repressor of growth hormone receptor gene expression: a unique noncatalytic role for a carboxyesterase protein. Mol Endocrinol 25:1351-63
Lu, Chunxia; Kumar, P Anil; Fan, Yong et al. (2010) A novel effect of growth hormone on macrophage modulates macrophage-dependent adipocyte differentiation. Endocrinology 151:2189-99
Kumar, P Anil; Kotlyarevska, Kateryna; Dejkhmaron, Prapai et al. (2010) Growth hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of gh with implications for the pathogenesis of diabetic nephropathy. J Biol Chem 285:31148-56
Thomas, Inas H; Saini, Natinder K; Adhikari, Amita et al. (2009) Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation. Pediatr Diabetes 10:492-6
Menon, R K; Shaufl, A; Yu, J H et al. (2001) Identification and characterization of a novel transcript of the murine growth hormone receptor gene exhibiting development- and tissue-specific expression. Mol Cell Endocrinol 172:135-46
Yu, J H; Schwartzbauer, G; Kazlman, A et al. (1999) Role of the Sp family of transcription factors in the ontogeny of growth hormone receptor gene expression. J Biol Chem 274:34327-36
Schwartzbauer, G; Menon, R K (1998) Regulation of growth hormone receptor gene expression. Mol Genet Metab 63:243-53
Schwartzbauer, G; Yu, J H; Cheng, H et al. (1998) Transcription factor MSY-1 regulates expression of the murine growth hormone receptor gene. J Biol Chem 273:24760-9

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