The Roles of FGF9 and FGF18 in Skeletal Development

描述（申请人提供）：骨骼发育不良是一种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，幸存者可能患有畸形和残疾，这严重影响了他们的生活数量和质量。颅缝闭锁和软骨发育不良是由成纤维细胞生长因子受体（Fgfrs）激活突变引起的骨骼发育不良，突出了FGF信号在膜性和软骨内骨发育中的关键作用。该候选人培养了缺乏Fgf9和Fgf18的小鼠，这些小鼠表现出严重的骨骼异常，包括颅骨明显发育不全，使她能够表征早期胚胎发生中的膜性骨发育。本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。这些研究的结果将增强我们对骨骼生物学中FGF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。

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.