Craniosynostosis is the morbid condition of premature fusion of calvarial bones. The sequelae of premature calvarial sutural fusion include 1) increased intracranial pressure associated with brain injury, 2) skull malformations requiring extensive surgical correction, and 3) abnormal development of the zygoma and maxilla necessitating orthodontic management and orthognatic surgery. Despite the rapid advance of our understanding of the molecular etiology of hereditary synostosis, the biological basis of craniosynostosis has yet to be elucidated. Over the past four years we have learned that mutations of fibroblast growth factor receptor family (FGFRs) and the TWIST are responsible for the majority of cases of syndromic synostosis. In order to understand the biology behind hereditary suture fusion, we propose to: 1) determine whether osteoblasts derived from patients with syndromic synostosis, harboring FGFR2, FGFR3, or TWIST mutations, will induce premature closure of rat coronal sutures 2) establish whether changes in suture development induced by mutant osteoblasts are due to intrinsic differences in mutant osteoblast growth and bone formation (e.g. cell autonomous) or the elaboration of cytokines which effect suture development and 3) correlate changes induced in suture development by mutant osteoblasts with changes in apoptotic cell death, mitogenic activity, and/or rates of matrix formation or mineralization. In order to test the hypothesis that: Syndromic craniosynostosis in humans is mediated by osteoblasts and their influence on the microenvironment of the calvarial suture. We propose that changes in osteoblast growth, mitotic rate, resistance to apoptosis and/or elaboration of cytokines results in premature suture fusion and craniosynostosis. These studies will lead to important information about the biology behind the development of craniosynostosis and may have significant implications for the treatment and primary prevention of synostosis in humans.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Comprehensive Center (P60)
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University of Washington
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Etikala, Anusha; Bruce, Greg; Hudkins, Kelly et al. (2017) LR8 Expression in fibroblasts of healthy and fibrotic human tissues. Biochem Biophys Rep 10:165-171
Yin, Lei; Chino, Takahiro; Horst, Orapin V et al. (2010) Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria. BMC Immunol 11:37
McKinney, Christy M; Cunningham, Michael L; Holt, Victoria L et al. (2009) A case-control study of infant, maternal and perinatal characteristics associated with deformational plagiocephaly. Paediatr Perinat Epidemiol 23:332-45
Coldwell, Susan E; Oswald, Teresa K; Reed, Danielle R (2009) A marker of growth differs between adolescents with high vs. low sugar preference. Physiol Behav 96:574-80
McKinney, Christy M; Holt, Victoria L; Cunningham, Michael L et al. (2008) Maternal and infant characteristics associated with prone and lateral infant sleep positioning in Washington state, 1996-2002. J Pediatr 153:194-8, 198.e1-3
McKinney, Christy M; Cunningham, Michael L; Holt, Victoria L et al. (2008) Characteristics of 2733 cases diagnosed with deformational plagiocephaly and changes in risk factors over time. Cleft Palate Craniofac J 45:208-16
Madan, Monica S; Liu, Zee J; Gu, Gao M et al. (2007) Effects of human relaxin on orthodontic tooth movement and periodontal ligaments in rats. Am J Orthod Dentofacial Orthop 131:8.e1-10
Pickrell, Jacqueline E; Heima, Masahiro; Weinstein, Philip et al. (2007) Using memory restructuring strategy to enhance dental behaviour. Int J Paediatr Dent 17:439-48
Mouradian, Wendy E; Huebner, Colleen E (2007) Future directions in leadership training of MCH professionals: cross-cutting MCH leadership competencies. Matern Child Health J 11:211-8
Mouradian, Wendy E (2006) Band-aid solutions to the dental access crisis: Conceptually flawed--a response to Dr. David H. Smith. J Dent Educ 70:1174-9

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