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: 9304184
• 负责人: Amy E Merrill
• 金额: $ 51.84万
• 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/9304184
• 关键词: Affect; Alpha Cell; Anabolism; Biogenesis; Birth; Cell Differentiation process; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cell Surface Receptors; Cell physiology; 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; 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; Physiologic Ossification; 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; new therapeutic target; novel; osteoprogenitor cell; promoter; public health relevance; 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.

 描述（由申请人提供）：骨骼异常影响很大一部分人口，每 3000 名新生儿中就有 1 例发生。许多骨骼出生缺陷是由决定骨骼祖细胞何时何地转变的基因突变造成的。成纤维细胞生长因子受体 2 (FGFR2) 是一种这样的基因，其突变至少是导致发育过程中终末分化的一种自我更新状态。颅面和肢体骨骼内表现出异常的 10 种不同疾病 FGFR2 通过调节骨祖细胞自我更新或分化的二元选择发挥着骨中关键信号传导节点的作用。然而，FGFR2 控制这些不同细胞的机制。该提案的总体目标是通过揭示核 FGFR2 调节核糖体生物发生的机制，更具体地了解 FGFR2 如何调节骨骼发育。核糖体的丰度调节细胞蛋白质合成的能力；核糖体组成的异质性调节翻译的特异性。mRNA 翻译成蛋白质是基因表达的真正终点，因为许多关键调节的 mRNA 和蛋白质水平存在差异。基因，通过核糖体生物发生控制翻译对于调节细胞生长、增殖和分化至关重要，有强有力的证据表明，在发育中的骨骼中进行这种控制，其中核糖体生物发生的减少与细胞的发病机制有关。我们发现了令人信服的证据，证明 FGFR2 紊乱弯曲骨发育不良综合征 (BBDS) 是由核糖体生物合成增加引起的。 FGFR2 介导的 rDNA 转录增加的限速步骤增加了核糖体的数量，并且是一致的。该提案将检验核 FGFR2 通过核糖体生物发生调节蛋白质合成来调节骨骼祖细胞发育的假设。在目标 1 中，我们将区分核和膜的确切作用。在目标 2 中，我们将定义核 FGFR2 如何调节骨骼祖细胞中的核糖体合成。确定增加的 rRNA 通过调节产生的蛋白质的特性和数量来调节骨骼祖细胞发育的程度，这一贡献将产生重大而广泛的影响，因为它将 1) 从根本上增进我们对 FGFR2 和核糖体引起的疾病机制的理解。功能障碍，包括出生缺陷和癌症，2) 为针对核 FGFR2 的治疗策略创造新的机会，并从本质上纠正这些疾病中的异常细胞增殖和分化。