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，幸存者可能患有畸形和残疾，严重影响他们的生活质量和数量。 颅缝早闭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，突出了FGF信号传导在膜和软骨内骨发育中的关键作用。 候选人已经产生了缺乏Fgf9和Fgf18的小鼠，这些小鼠表现出严重的骨骼异常，包括颅骨的显著发育不全，使她能够表征早期胚胎发生中的膜骨发育。 本申请将探索FGF 9和FGF 18调节膜骨形成的机制，使用小鼠颅骨发育作为模型系统。 这些研究的结果将增强我们对骨骼生物学中FGF信号传导的理解，并可能促进骨骼发育不良患者治疗策略的发展。 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是调节膜性骨发育的关键FGF配体。 因此，提出了以下具体目标：1。确定FGF 9和FGF 18信号传导调节颅骨发育和膜骨形成的细胞机制，以及2.定义颅骨发育和膜骨形成中的分子信号网络。 一个结构良好的职业发展计划，广泛支持机构资源和国际知名的导师，已经设计，让候选人在K奖的任期内过渡到一个独立的终身教职研究员。 因此，她将接受必要的培训，以指导积极的研究计划，并提供最先进的临床护理。 相关性：骨骼发育不良是一组重要的先天性出生缺陷，可以深刻影响儿童的生活质量和数量。 从这些拟议的研究中产生的数据将增强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骼疾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.