EXCEED THE SPACE PROVIDED. Insulin-like growth factor-I (IGF-I), a conserved 70-residue secreted protein, plays a fundamental role in somatic growth in mammals and other vertebrate species. Although much evidence has accumulated supporting IGF-I as a major postnatal growth factor, regulated at least in part by growth hormone, many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth, maintenance, and repair throughout the life span. These observations in turn imply that control of IGF-I synthesis may be multi-factorial, responding not only to systemic hormonal signals but also to tissue- specific factors. IGF-I is produced by many cells including osteoblasts, and can act as a growth and differentiation factor within the skeleton as well as in other tissues. Recent studies implicating IGF-I as a key component of the anabolic effects of parathyroid hormone (PTH) on bone and establishing a role for PTH in increasing bone mass and preventing osteoporosis only underscore the importance of IGF-I in maintaining skeletal integrity. Since osteoporosis is a disorder of remodeling in which bone resorption outstrips formation, any insights into pathways that enhance bone mass have potential therapeutic implications. As part of a long-term effort to understand the mechanisms by which IGF-I synthesis is controUed under different physiological conditions, the focus of this application will be on regulation of IGF-I gene transcription in bone cells. Key goals will be to define the signal transduction pathways and molecular mechanisms by which PTH through cyclic AMP and protein kinase A controls IGF-t expression via the transcription factor, C/EBPdelta. Toward this end the following four Specific Aims are proposed: 1. To determine how PKA activates CIEBPdelta and stimulates its nuclear expression in osteoblasts. 2. To establish how PKA promotes the transcriptional activity of C/EBPdelta in bone cells. 3. To define mechanisms of termination of hormone-activated IGF-I transcription and down regulation of C/EBPdelta activity in osteoblasts. 4. To evaluate by gene profiling the role of C/EBPdelta in osteoblast biology. PERFORMANCE SiTE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Endocrinology Study Section (END)
Program Officer
Malozowski, Saul N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Varco-Merth, Benjamin; Feigerlová, Eva; Shinde, Ujwal et al. (2013) Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity. Mol Endocrinol 27:150-61
Mukherjee, Aditi; Rotwein, Peter (2009) Akt promotes BMP2-mediated osteoblast differentiation and bone development. J Cell Sci 122:716-26
Mukherjee, Aditi; Wilson, Elizabeth M; Rotwein, Peter (2008) Insulin-like growth factor (IGF) binding protein-5 blocks skeletal muscle differentiation by inhibiting IGF actions. Mol Endocrinol 22:206-15
Mukherjee, Aditi; Rotwein, Peter (2008) Insulin-like growth factor-binding protein-5 inhibits osteoblast differentiation and skeletal growth by blocking insulin-like growth factor actions. Mol Endocrinol 22:1238-50
Kuninger, David; Lundblad, James; Semirale, Anthony et al. (2007) A non-isotopic in vitro assay for histone acetylation. J Biotechnol 131:253-60
Mukherjee, Aditi; Rotwein, Peter (2007) Insulin-like growth factor binding protein-5 in osteogenesis: facilitator or inhibitor? Growth Horm IGF Res 17:179-85
Chia, Dennis J; Ono, Mitsuru; Woelfle, Joachim et al. (2006) Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. J Biol Chem 281:3190-7
Chia, Dennis J; Subbian, Ezhilkani; Buck, Teresa M et al. (2006) Aberrant folding of a mutant Stat5b causes growth hormone insensitivity and proteasomal dysfunction. J Biol Chem 281:6552-8