REGULATION OF SKELETAL DEVELOPMENT BY PERK eIF2-ALPHA KINASE

PERK eIF2-α 激酶对骨骼发育的调节

• 批准号: 7196420
• 负责人: DOUGLAS R. CAVENER
• 金额: $ 30.04万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196420
• 关键词: Address; Biochemical; Bone and Cartilage Funding; Cells; Chondrocytes; Collagen; Collagen Type I; Coupled; Defect; Embryo; Epiphysial cartilage; Event; Extracellular Matrix; Fibroblasts; Future; Gene Expression; Generations; Genes; Goals; Growth; Growth and Development function; Hereditary Disease; Human; Hydroxylation; Knock-out; Knockout Mice; Link; Localized; Molecular; Mus; Mutation; Nature; Osteoblasts; Osteoporosis; Pathway interactions; Peptide Initiation Factors; Phosphotransferases; Process; Procollagen; Proline; Protein Biosynthesis; Proteins; Regulation; Research Personnel; Role; Secretory Cell; Skeletal Development; Skeletal system; Tissues; Transgenes; Transgenic Organisms; Type I Procollagen; Wolcott-Rallison syndrome; base; extracellular; long bone; postnatal; programs; research study; secretory protein; skeletal dysplasia; tibia

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.

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，因为软骨和骨大部分位于细胞外，并由胶原蛋白和各种其他分泌蛋白组成。胶原蛋白和非胶原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，人们对分泌蛋白的合成及其分泌的调节如何在这些细胞中耦合知之甚少。我们已经证明，PERK eIF2α 激酶是关键翻译起始因子的调节因子，对于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剂。我们建议确定 PERK 依赖性调节 I 型胶原合成和分泌的机制，识别 Perk-/- 小鼠生长板肥大区细胞外基质缺陷的分子缺陷，并确定 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，Wolcott-Rallison 综合征是一种与人类 Perk 基因相关的遗传疾病，表现出与 Perk-/- 基因敲除小鼠相同的一系列骨骼缺陷。