Skeletal development, growth and remodeling are highly dependent upon the dynamic regulation of protein synthesis and secretion inasmuch as cartilage and bone are largely extracellular and composed of collagens plus a variety of other secreted proteins. The synthesis and secretion of collagens and noncollagenous extracellular matrix arise from the major secretory cells of the skeletal system, osteoblasts and chondrocytes. Currently little is known of how the regulation of synthesis of secretory proteins and their secretion are coupled in these cells. We have shown that the PERK eIF2alpha kinase, a regulator of a key translation initiation factor, is essential for the development and growth of the skeletal system. We postulate that PERK is a key regulator of molecular events that control the secretory processes of chondrocytes and osteoblasts. We propose to determine the mechanism of PERK-dependent regulation of type I collagen synthesis and secretion, to identify the molecular defects that underlie the deficient extracellular matrix in the hypertrophic zone in the growth plate of Perk-/- mice, and to determine the cellular basis of the skeletal dysplasias observed in the Perk-/- knockout mice. These studies are directly related to understanding the molecular basis of osteoporosis in the human Wolcott-Rallison syndrome, a genetic disease linked to the human Perk gene that shows the same array of skeletal defects seen in the Perk-/- knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR049816-01A1
Application #
6731014
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Sharrock, William J
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2004-03-15
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$316,800
Indirect Cost
Name
Pennsylvania State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Wei, Jianwen; Sheng, Xiaoyi; Feng, Daorong et al. (2008) PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol 217:693-707
Wek, Ronald C; Cavener, Douglas R (2007) Translational control and the unfolded protein response. Antioxid Redox Signal 9:2357-71
Iida, Kaori; Cox-Foster, Diana L; Yang, Xiaolong et al. (2007) Expansion and evolution of insect GMC oxidoreductases. BMC Evol Biol 7:75