REGULATION OF SKELETAL DEVELOPMENT BY PERK eIF2-ALPHA KINASE

描述（由申请人提供）：骨发育、生长和重塑高度依赖于蛋白质合成和分泌的动态调节，因为软骨和骨主要是细胞外的，并且由胶原蛋白加上多种其他分泌蛋白组成。胶原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，很少有人知道如何在这些细胞中的分泌蛋白的合成和分泌的调控耦合。我们已经表明，PERK eIF 2 α激酶，一个关键的翻译起始因子的调节，是必不可少的骨骼系统的发育和生长。我们假设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，以确定的机制PERK依赖的调节I型胶原蛋白的合成和分泌，以确定的分子缺陷的基础上缺乏细胞外基质在肥大区的生长板的Perk-/-小鼠，并确定在Perk-/-敲除小鼠中观察到的骨骼发育不良的细胞基础。这些研究与理解人类Wolcott-Rallison综合征中骨质疏松症的分子基础直接相关，这是一种与人类Perk基因相关的遗传疾病，显示出与Perk-/-敲除小鼠相同的骨骼缺陷阵列。

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.