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

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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.