The Roles of FGF9 and FGF18 in Skeletal Development

描述(申请人提供)：骨骼发育不良是一组重要的先天性出生缺陷。患有这些疾病的儿童可能在婴儿期死亡，幸存者可能患有严重影响其生活数量和质量的畸形和残疾。颅骨融合和软骨发育不良是由成纤维细胞生长因子受体(FGFRs)的激活突变引起的骨骼发育不良，突显出成纤维细胞生长因子信号在膜骨和软骨内骨发育中的关键作用。这位候选人已经培育出同时缺乏Fgf9和Fgf18的小鼠，这些小鼠表现出严重的骨骼异常，包括显著的颅骨发育不全，使她能够表征早期胚胎发育中的膜性骨骼发育。这项应用将以小鼠颅骨发育为模型系统，探索FGF9和FGF18调节膜性骨形成的机制。这些拟议的研究结果将加深我们对骨骼生物学中的成纤维细胞生长因子信号的理解，并可能促进骨骼发育不良患者治疗策略的发展。 这位候选人的长期目标是了解调节骨骼生物学的遗传途径。她假设FGF9和FGF18是调节膜骨发育的关键的成纤维细胞生长因子配体。因此，提出了以下具体目标：1.确定成纤维细胞生长因子9和18信号调节颅骨发育和膜骨形成的细胞机制(S)；2.确定颅骨发育和膜骨形成中的分子信号网络。 在机构资源和国际知名导师的广泛支持下，设计了一个结构良好的职业发展计划，使候选人能够在K奖项的任期内过渡到独立的终身教职跟踪教研员。因此，她将接受必要的培训，以指导积极的研究计划和提供最先进的临床护理。 相关：骨骼发育不良是一组重要的先天性出生缺陷，可深刻影响儿童的生活质量和数量。这些拟议研究产生的数据将加深我们对骨骼生物学分子机制的理解，并可能促进骨骼发育不良和其他骨病患者治疗策略的发展。

DESCRIPTION (Provided by Applicant): Skeletal dysplasias constitute an important group of congenital birth defects. Children with these disorders may die in infancy, and survivors may have malformations and disabilities that significantly impact their quantity and quality of life. Craniosynostosis and chondrodysplasias are skeletal dysplasias caused by activating mutations in fibroblast growth factor receptors (Fgfrs), highlighting the critical role of FGF signaling in both membranous and endochondral bone development. The candidate has generated mice lacking both Fgf9 and Fgf18 that show severe skeletal abnormalities, including striking agenesis of the calvarial bones, enabling her to characterize membranous bone development in early embryogenesis. This application will explore the mechanisms by which FGF9 and FGF18 regulate membranous bone formation, using murine calvarial development as a model system. The results of these proposed studies will enhance our understanding of FGF signaling in skeletal biology, and may promote the development of treatment strategies for patients with skeletal dysplasias. The candidate's long-term objective is to understand the genetic pathways that regulate skeletal biology. She hypothesizes that FGF9 and FGF18 are critical FGF ligands that regulate membranous bone development. Thus the following specific aims are proposed: 1. Determine the cellular mechanism(s) by which FGF9 and FGF18 signaling regulate(s) calvarial development and membranous bone formation, and 2. Define molecular signaling networks in calvarial development and membranous bone formation. A well structured career development plan, extensively supported with institutional resources and internationally known mentors, has been designed to allow the candidate to transition during the tenure of the K award to an independent tenure-track faculty investigator. Thus, she will receive the necessary training both to direct an active research program and to provide state-of-the-art clinical care. RELEVANCE: Skeletal dysplasias constitute an important group of congenital birth defects that can profoundly impact quantity and quality of life for children. The data generated from these proposed studies will enhance our understanding of molecular mechanisms in skeletal biology and may promote the development of treatment strategies for patients with skeletal dysplasias and other bone disorders.