Functions of fibroblast growth factor receptors

成纤维细胞生长因子受体的功能

• 批准号: 8349845
• 负责人: Chuxia Deng
• 金额: $ 46.58万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349845
• 关键词: Affinity; Amino Acids; Apert syndrome; Biological Process; Craniosynostosis; Defect; Development; Disease; Exhibits; FGFR1 gene; FGFR2 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Targeting; Genes; Growth Factor; Human; Human Genome; Inherited; Knock-out; Live Birth; Malignant Neoplasms; Mediating; Membrane; Messenger RNA; Mus; Mutant Strains Mice; Mutation; Patients; Phenotype; Play; Point Mutation; Protein Isoforms; Protein Tyrosine Kinase; Reporting; Role; Signal Transduction; System; Testing; bone; craniofacial; gain of function; human disease; inhibitor/antagonist; insight; mouse model; mutant; prevent; receptor; restoration; skeletal disorder; small hairpin RNA

Here we report our study on one of the skeletal diseases, the Apert syndrome, which occurs at one in 65,000 live births in human. We first introduced a Ser252Trp mutation that is found in human Apert patients, to mouse FGFR2 gene. The FGFR2-Ser252Trp mutant mice displayed phenotypes mimicking the human Apert disease. We then use this mouse model to test preventivetherapeutic approaches to see if the disease can be prevented or cured. We show that a small hairpin RNA (shRNA), targeting the FGFR2-S252W mutant form mRNA in this mouse model, completely inhibits Apert-like craniosynostosis and the related defects. We further show that restoration of normal FGFR2 signaling is manifested by an alteration of ERK12 activity, implicating ERK and its downstream genes in disease expressivity. Furthermore, treatment of mutant mice with an ERK inhibitor results in a complete cure of mutant phenotypes. These results illustrate an unknown pathogenic role of ERK activation in the FGFR2-S252W-associated craniosynostosis and represent a new concept of shRNA-mediated therapy for diseases caused by gain of functions associated with activating point mutations in human genome.

在这里，我们报告了有关一种骨骼疾病APERT综合征的研究，该综合症发生在人类中的65,000例活生生中。我们首先引入了在人APERT患者中发现的SER252TRP突变，该突变引入了小鼠FGFR2基因。 FGFR2-SER252TRP突变小鼠表现出模仿人类APERT疾病的表型。然后，我们使用该小鼠模型测试预防性方法，以查看是否可以预防或治愈该疾病。我们表明，在该小鼠模型中靶向FGFR2-S252W突变体形式mRNA的小发夹RNA（SHRNA）完全抑制了APERT样的颅骨流症和相关缺陷。我们进一步表明，正常FGFR2信号传导的恢复是由ERK12活性的改变表现出来的，这意味着ERK及其下游基因在疾病表现上。此外，用ERK抑制剂治疗突变小鼠会导致突变表型的完全治愈。这些结果说明了ERK激活在FGFR2-S252W相关的颅骨突变中的未知致病作用，并代表了由与人类基因组激活点突变相关的功能获得的shRNA介导的疾病的新概念。