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: 7383821
• 负责人: DOUGLAS R. CAVENER
• 金额: $ 29.44万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383821
• 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，因为软骨和骨骼在很大程度上是细胞外的，并且由胶原蛋白以及其他各种分泌的蛋白质组成。胶原蛋白和非胶原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，几乎不知道如何在这些细胞中耦合分泌蛋白的合成及其分泌。我们已经表明，PERK EIF2Alpha激酶是关键翻译起始因子的调节剂，对于骨骼系统的发展和生长至关重要。我们假设PERK是控制软骨细胞和成骨细胞的分泌过程的分子事件的关键调节剂。我们建议确定I型胶原蛋白合成和分泌的PERK依赖性调节的机制，以确定在PERK-/ - 鼠的生长板中肥厚区域中缺乏细胞外基质的分子缺陷，并确定在Perk-opkk - /-/---敲除骨骼骨骼骨骼骨骼的细胞基础上的细胞基础。这些研究直接与理解人类沃尔科特 - 里森综合症中骨质疏松症的分子基础有关，这是一种与人类PERK基因相关的遗传疾病，该疾病显示出在PERK - / - 敲除小鼠中看到的一系列骨骼缺陷。