Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion, resulting in abnormal skull shape, blindness and mental retardation. The prevalence of craniosynostosis is at 1 in 2,500 live births, which is one of the highest incidences of congenital malformation of skeletal system. The long-term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies demonstrated that craniosynostosis is associated with mutations in FGF signaling components, Twist, Msx2 and Efnb1, however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of-function mutation in a BMP signaling component. This model is unique and important because 1) upregulation of FGF signaling is observed, 2) ectopic cartilage is formed at the site of fusion prior to the fusion, and 3) the phenotype is rescued in heterozygous null background of BMPRIA, indicating that the precise control of BMP signaling is critical to prevent craniosynostosis. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.

Public Health Relevance

In this proposal, we will define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of- function mutation in a BMP signaling component. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE020843-02
Application #
8064718
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Lumelsky, Nadya L
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$374,663
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shi, Ce; Mandair, Gurjit S; Zhang, Honghao et al. (2018) Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition. J Struct Biol 201:237-246
Cholok, David; Chung, Michael T; Ranganathan, Kavitha et al. (2018) Heterotopic ossification and the elucidation of pathologic differentiation. Bone 109:12-21
Fu, Liye; Simakova, Antonina; Fantin, Marco et al. (2018) Direct ATRP of Methacrylic Acid with Iron-Porphyrin Based Catalysts. ACS Macro Lett 7:26-30
Liu, Xia; Hayano, Satoru; Pan, Haichun et al. (2018) Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death. Genesis 56:e23093
Kwon, Edwin K; Louie, Ke'ale; Kulkarni, Anshul et al. (2018) The Role of Ellis-Van Creveld 2(EVC2) in Mice During Cranial Bone Development. Anat Rec (Hoboken) 301:46-55
Kulkarni, Anshul K; Louie, Ke'ale W; Yatabe, Marilia et al. (2018) A Ciliary Protein EVC2/LIMBIN Plays a Critical Role in the Skull Base for Mid-Facial Development. Front Physiol 9:1484
Sun, Xuefei; Zhu, Weipu; Matyjaszewski, Krzysztof (2018) Protection of opening lids: very high catalytic activity of lipase immobilized on core-shell nanoparticles. Macromolecules 51:289-296
Kramer, Kaitrin; Yang, Jingwen; Swanson, W Benton et al. (2018) Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model. Genesis 56:e23220
Li, Sipei; Chung, Hee Sung; Simakova, Antonina et al. (2017) Biocompatible Polymeric Analogues of DMSO Prepared by Atom Transfer Radical Polymerization. Biomacromolecules 18:475-482
Agarwal, Shailesh; Loder, Shawn J; Breuler, Christopher et al. (2017) Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Mol Ther 25:1974-1987

Showing the most recent 10 out of 65 publications