The development of the Face Base Consortium calls for a comprehensive research collaboration to facilitate data collection, organization, and optimized utilization of new and existing data on mid-facial development and malformations. Our laboratory has a long history of investigating the molecular and cellular mechanism of cleft palate. We have developed a proposal that builds on our strength and will focus on genomic and imaging analysis of selected and highly clinically relevant cleft palate animal models. Specifically, we will use the Tgfb, Tgfbr, Smad4, Msx1 and Fgfr2 mutant animal models that represent complete and sub-mucous cleft palate defects in humans as our entry point. Taking advantage of these animal models, we will work closely with several scientists to address the regulatory mechanism of CNC cell fate determination. Specifically, working with Dr. Marianne Bronner-Fraser at California Institute of Technology (Caltech), we will investigate whether the neural crest gene regulatory network of traditional vertebrate models is conserved and may exert its regulatory function during palatogenesis. In collaboration with Dr. Joseph Hacia at USC, we will discover critical components of the Tgf-b signaling network that are specifically involved in regulating the fate of CNC cells during palatogenesis. Working with Dr. Scott Fraser at Caltech, we will generate comprehensive and dynamic three-dimensional images of palatogenesis and malformations using microMRI and microCT. Finally, we have developed a strategy to screen for specific points of intervention within the gene regulatory network that will allow us to develop therapeutic strategies to prevent and rescue cleft palate. Our collective effort will not only generate tremendous resources for the Face Base Consortium but will also offer opportunities for extensive collaborations for future translational research on craniofacial birth defects.

Public Health Relevance

Cleft palate represents one of the most common congenital birth defects in the human population. Through a collaborative approach, this research program is designed to investigate the signaling mechanism of cleft palate and to provide crucial genomic and imaging resources for future cleft palate research. More importantly, this proposal will reveal crucial points of intervention, which can be targeted for future prevention and rescue of cleft palate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DE020065-05
Application #
8463414
Study Section
Special Emphasis Panel (ZDE1-JH (24))
Program Officer
Scholnick, Steven
Project Start
2009-09-21
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$391,329
Indirect Cost
$208,304
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhao, Hu; Feng, Jifan; Seidel, Kerstin et al. (2014) Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14:160-73
Iwata, Jun-ichi; Suzuki, Akiko; Yokota, Toshiaki et al. (2014) TGF? regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate. Development 141:909-17
Iwata, Junichi; Suzuki, Akiko; Pelikan, Richard C et al. (2014) Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice. Hum Mol Genet 23:182-93
Iwata, Jun-ichi; Suzuki, Akiko; Pelikan, Richard C et al. (2013) Smad4-Irf6 genetic interaction and TGFýý-mediated IRF6 signaling cascade are crucial for palatal fusion in mice. Development 140:1220-30
Iwata, Jun-ichi; Suzuki, Akiko; Pelikan, Richard C et al. (2013) Noncanonical transforming growth factor * (TGF*) signaling in cranial neural crest cells causes tongue muscle developmental defects. J Biol Chem 288:29760-70
Pelikan, Richard C; Iwata, Junichi; Suzuki, Akiko et al. (2013) Identification of candidate downstream targets of TGFýý signaling during palate development by genome-wide transcript profiling. J Cell Biochem 114:796-807
Parada, Carolina; Li, Jingyuan; Iwata, Junichi et al. (2013) CTGF mediates Smad-dependent transforming growth factor * signaling to regulate mesenchymal cell proliferation during palate development. Mol Cell Biol 33:3482-93
Han, Dong; Zhao, Hu; Parada, Carolina et al. (2012) A TGF*-Smad4-Fgf6 signaling cascade controls myogenic differentiation and myoblast fusion during tongue development. Development 139:1640-50
Iwata, Jun-ichi; Hacia, Joseph G; Suzuki, Akiko et al. (2012) Modulation of noncanonical TGF-* signaling prevents cleft palate in Tgfbr2 mutant mice. J Clin Invest 122:873-85
Iwata, J; Parada, C; Chai, Y (2011) The mechanism of TGF-* signaling during palate development. Oral Dis 17:733-44

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