Role of a craniosynostosis associated fibroblast growth factor receptor mutation in extraocular muscles

项目总结 颅缝早闭综合征是一组破坏性的发育障碍，其特征是 头面部异常和斜视，或眼睛错位。最常见的颅缝早闭综合征， 包括Apert综合征在内，均与成纤维细胞生长因子受体2(FGFR2)基因突变有关。 由于手术失败率高，Apert综合征患者的斜视很难治疗。可悲的是，没有得到治疗 斜视与弱视、视力丧失以及显著的功能和心理社会密切相关 对患者的生活质量产生负面影响的困难。 目前尚不清楚FGFR2信号异常与Apert患者斜视的关系 综合症。这些患者有异常的骨性眼眶和异常的眼外肌(EOM)，因为 已知的FGFR2突变；然而，目前还不清楚异常的FGFR2信号，异常的骨骼轨道， EOM异常临床表现为斜视。先前的研究表明非典型的EOM，特别是 在人类Apert患者和Apert小鼠模型中，较小的EOM和肌纤维紊乱。 科学调查的重点将是确定导致EOM异常的决定因素 Apert综合征的结构和功能以及导致EOM疾病的关键因素 阿佩特综合征。将使用MRI、组织学和肌肉功能来分析EOM的解剖和功能 学习。仅在肌肉、肌肉干细胞、骨骼或神经中表达FGFR2突变的突变小鼠 神经元将被用来表征不同组织中异常的FGFR2信号对改变的贡献 Apert综合征的Eom结构和功能。一种针对FGFR2异常的新型基因治疗 Apert综合征的突变也将在我们的Apert小鼠模型中使用类似的技术进行测试。 鲁德尔博士提出了一项职业发展计划，以实现她成为独立人士的目标 临床科学家，在EOM生理学方面具有专业知识。她在突触发育方面的研究背景 骨骼肌与她在儿科眼科和EOM疾病中的临床兴趣完美地相交。她 部门非常支持她在加州大学圣地亚哥分校的职业目标，可以访问 优秀的导师和研究设施。她的职业发展计划包括课程学习和实践。 遗传学和肌肉生物力学的研究项目。她的导师是一流的科学家和临床医生 肌肉生理学、颅面遗传学和儿科眼科，有出色的训练记录。他们是 毫不含糊地致力于鲁德尔博士作为一名独立临床科学家的成功。

PROJECT SUMMARY Craniosynostosis syndromes are a group of devastating developmental disorders characterized by craniofacial abnormalities and strabismus, or eye misalignment. The most common craniosynostosis syndromes, including Apert Syndrome, are associated with genetic mutations in fibroblast growth factor receptor 2 (Fgfr2). Strabismus in Apert syndrome patients is difficult to treat due to high surgical failure rates. Sadly, untreated strabismus is closely correlated with amblyopia, vision loss, and significant functional and psychosocial difficulties that negatively impact quality of life for patients. It is unclear how abnormal FGFR2 signaling is associated with strabismus in patients with Apert syndrome. These patients have abnormal bony orbits and abnormal extraocular muscles (EOM) because of a known Fgfr2 mutation; however, it is not well understood how abnormal FGFR2 signaling, abnormal bony orbits, and abnormal EOM clinically manifest as strabismus. Previous research shows atypical EOM, specifically smaller EOM and myofiber disorganization, in both human Apert patients and in the Apert mouse model. Scientific investigations will focus on identifying the contributing determinants that govern abnormal EOM structure and function in Apert syndrome and the key factors that cause EOM disease using a mouse model for Apert syndrome. EOM anatomy and function will be analyzed using MRI, histology, and muscle functional studies. Mutant mice that only express the Fgfr2 mutation in muscle, muscle stem cells, bone, or innervating neurons will be used to characterize the contributions of abnormal FGFR2 signaling in different tissues to altered EOM structure and function in Apert syndrome. A novel gene therapy that specifically targets the abnormal Fgfr2 mutation in Apert syndrome will also be tested in our Apert mouse model using similar techniques. Dr. Rudell has proposed a career development plan to reach her goal of becoming an independent clinician scientist with an expertise in EOM physiology. Her research background in synaptic development in skeletal muscle intersects perfectly with her clinical interests in pediatric ophthalmology and EOM disease. Her department is extremely supportive of her career goals at the University of California San Diego, with access to outstanding mentors and research facilities. Her career development plan includes coursework and hands-on research projects in genetics and muscle biomechanics. Her mentors are leading scientists and clinicians in muscle physiology, craniofacial genetics, and pediatric ophthalmology, with excellent training records. They are unequivocally committed to Dr. Rudell’s success as an independent clinician scientist.