REGULATION OF SKELETAL DEVELOPMENT BY PERK eIF2-ALPHA KINASE

描述(申请人提供)：骨骼的发育、生长和重塑高度依赖于蛋白质合成和分泌的动态调节，因为软骨和骨骼主要是细胞外的，由胶原蛋白和各种其他分泌的蛋白质组成。胶原蛋白和非胶原性细胞外基质的合成和分泌来自骨骼系统的主要分泌细胞、成骨细胞和软骨细胞。目前，关于分泌蛋白的合成及其分泌的调控在这些细胞中是如何耦合的，人们知之甚少。我们已经证明，PERK eIF2α激酶是一个关键的翻译起始因子的调节因子，对于骨骼系统的发育和生长是必不可少的。我们推测，PERK是控制软骨细胞和成骨细胞分泌过程的分子事件的关键调节因子。我们建议确定PERK依赖的I型胶原合成和分泌的调节机制，确定PERK-/-小鼠生长板肥大带细胞外基质缺乏的分子缺陷，并确定在PERK/-基因敲除小鼠中观察到的骨骼发育不良的细胞学基础。这些研究直接关系到了解人类Wolcott-Rallison综合征骨质疏松症的分子基础，这是一种与人类PERK基因相关的遗传病，显示出与PERK/-基因敲除小鼠相同的一系列骨骼缺陷。

DESCRIPTION (provided by applicant): 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.