REGULATION OF SKELETAL DEVELOPMENT BY PERK eIF2-ALPHA KINASE

描述（由申请人提供）：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蛋白组成。胶原和非胶原细胞外基质的合成和分泌来源于骨骼系统的主要分泌细胞，成骨细胞和软骨细胞。目前对这些细胞中分泌蛋白的合成调控及其分泌是如何耦合的知之甚少。我们已经证明PERK eif2 α激酶是一种关键翻译起始因子的调节因子，对骨骼系统的发育和生长至关重要。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。我们拟确定Perk依赖性调节I型胶原合成和分泌的机制，确定导致Perk-/-小鼠生长板肥厚区细胞外基质缺陷的分子缺陷，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。这些研究与了解人类Wolcott-Rallison综合征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，在Perk-/-敲除小鼠中显示出相同的骨骼缺陷。

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.