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.

 描述（由适用提供）：骨骼异常会影响大部分人口，每3000例出生的事件率为1例。由于基因的突变定义了何时何地，骨骼祖细胞从自我更新状态转变为发育过程中末端分化的一种，因此出现了许多骨骼出生缺陷。成纤维细胞生长因子受体2（FGFR2）就是这样的基因，其突变是导致至少10种不同的疾病，这些疾病暴露了颅面AD肢体骨骼内的异常。 FGFR2通过控制骨基源细胞的二元选择以自我更新或分化来充当骨骼中的关键信号节点。但是，FGFR2控制这些独特的细胞结局的机制尚不完全了解。该提案的总体目的是通过揭示核FGFR2调节核糖体生物发生的机制来了解FGFR2如何调节骨骼发育的更具体性。核糖体的抽象调节细胞的蛋白质合成能力。核糖体组成的异质性调节翻译的特异性。将mRNA转化为蛋白质是基因表达的真实终点，并且因为许多关键调节基因的mRNA和蛋白质水平之间存在差异，所以通过核糖体生物发生控制翻译对于控制细胞生长，增殖和分化至关重要。在发育中的骨骼中，有强有力的证据表明，在骨骼异常的发病机理中实现了改善的核糖体生物发生。我们发现了令人信服的证据，表明FGFR2-疾病弯曲骨发育不良综合征（BBD）是由核糖体生物发生增加引起的。我们发现，BBD中的突变增强了FGFR2在核olus中激活rDNA转录的正常活性，RDNA转录是构建核糖体的速率限制步骤。 FGFR2介导的rDNA转录增加增加了核糖体的数量，并且与增殖的兴起相吻合，牺牲了骨基源细胞的分化。该建议将检验以下假设：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的发育。在AIM 1中，我们将区分骨形成过程中核和膜FGFR2信号的精确作用。在AIM 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。在AIM 3中，我们将通过调节产生的蛋白质的同一性和量来确定增加rRNA在多大程度上调节骨骼祖细胞的发展。这项贡献将产生重大和广泛的影响，因为它将1）从根本上提高我们对由FGFR2和核糖体功能障碍引起的机制的理解，包括先天缺陷和癌症，以及2）2）为靶向核FGFR2的治疗策略创造了新的机会，这些策略靶向核FGFR2，并在这些疾病中进行了异常正确的细胞扩散和分化。