THE ROLE OF FGFR2 IN PROTEIN SYNTHESIS DURING SKELETAL DEVELOPMENT

FGFR2 在骨骼发育过程中蛋白质合成中的作用

• 批准号: 9097692
• 负责人: Amy E Merrill
• 金额: $ 43.75万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097692
• 关键词: Affect; Anabolism; Biogenesis; Birth; Cell Differentiation process; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cell Surface Receptors; Cell surface; Cells; Chromatin; Congenital Abnormality; Data; Defect; Development; Developmental Bone Diseases; Disease; Epigenetic Process; Equilibrium; Exhibits; FGF2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genetic Translation; Genetic study; Goals; Health; Heterogeneity; Incidence; Knockout Mice; Knowledge; Ligands; Limb structure; Link; Malignant Neoplasms; Mediating; Membrane; Messenger RNA; Mutation; Nuclear; Nuclear Envelope; Osteogenesis; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Population; Protein Biosynthesis; Proteins; Regulator Genes; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Skeletal Development; Skeleton; Specificity; Stem cells; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Translations; Work; bone; cell growth; cell type; craniofacial; extracellular; gene repression; novel; osteoprogenitor cell; promoter; rRNA Precursor; receptor; self-renewal; skeletal; skeletal disorder

 DESCRIPTION (provided by applicant): Skeletal anomalies affect a significant proportion of the population, with an incidence rate of 1 case per 3000 births. Numerous skeletal birth defects arise as a consequence of mutations in genes that define when and where skeletal progenitor cells transition from a self-renewing state to one of terminal differentiation during development. Fibroblast Growth Factor Receptor 2 (FGFR2) is one such gene whose mutations are responsible for at least 10 distinct disorders that exhibit abnormalities within the craniofacial ad limb skeleton. FGFR2 acts as a key signaling node in bone by regulating the binary choice of osteoprogenitor cells to either self-renew or to differentiate. However, the mechanism by which FGFR2 controls these distinct cellular outcomes is not completely understood. The overall objective of this proposal is to understand with much greater specificity how FGFR2 regulates skeletal development by revealing the mechanism through which nuclear FGFR2 regulates ribosome biogenesis. The abundance of ribosomes regulates a cell's capacity for protein synthesis; heterogeneities in the composition of ribosomes regulate specificity in translation. Translation of mRNA into protein is the true endpoint of gene expression and because there is a discrepancy between mRNA and protein levels for many key regulatory genes, controlling translation through ribosome biogenesis is critical in regulating cell growth, proliferation, and differentiation. There is strong evidence for such control in the developing skeleton where decreased ribosome biogenesis is implicated in the pathogenesis of skeletal anomalies. We have uncovered compelling evidence that the FGFR2-disorder Bent Bone Dysplasia Syndrome (BBDS) is cause by increased ribosome biogenesis. We found that the mutations in BBDS enhance a normal activity for FGFR2 in the nucleolus where it activates rDNA transcription, the rate-limiting step in building ribosomes. FGFR2-mediated increase in rDNA transcription elevates the number of ribosomes and is coincident with an upsurge in proliferation at the expense of differentiation in osteoprogenitor cells. This proposal will test the hypothesis that nuclear FGFR2 regulates skeletal progenitor cell development by modulating protein synthesis via ribosome biogenesis. In Aim 1, we will distinguish the precise roles of nuclear and membrane FGFR2 signaling during bone formation. In Aim 2, we will define how nuclear FGFR2 regulates ribosome synthesis in skeletal progenitor cells. In Aim 3, we will determine the extent to which increased rRNA regulates development of skeletal progenitor cells by modulating the identity and amount of proteins produced. This contribution will have significant and broad impact because it will 1) fundamentally advance our understanding of the mechanisms underpinning diseases caused by FGFR2 and ribosome dysfunction, including birth defects and cancer, and 2) create new opportunities for therapeutic strategies that target nuclear FGFR2 and intrinsically correct aberrant cell proliferation and differentiation in these diseases.