Cleft lip and palate (CLP) is one of the most common congenital malformations in humans. Its high incidence and prolonged multidisciplinary management protocols place considerable burden on health care systems worldwide, and significant psychological and financial burden on patients and their families. CLP is thought to arise as a result of the combination of both a genetic susceptibility and adverse environmental conditions in the sixth week of gestation. Although much progress has been made in identifying genes associated with the presentation of CLP, there is still relatively little known about how they all function to orchestrate normal lip and palate development. This proposal aims to understand the role of a small family of cell adhesion proteins, the nectins, in the normal process of lip and palate formation using the chick embryo as the model system. We will also delineate the cellular processes perturbed by deficiencies of these nectins that we hypothesize predisposes the developing fetus to CLP. To achieve this, we will utilize a variety of powerful new genetic technologies developed to specifically modulate target gene expression in pre-fusion orofacial epithelia in ovo and in facial explant cultures, with phenotypic consequences quantitatively assessed using different multidimensional imaging modalities. These approaches should overcome some of the limitations that have hindered progress in this field and provide a powerful tool in the analysis of nectin function in facial morphogenesis and the predisposition to CLP.

Public Health Relevance

Around one in 600 children are born with cleft lip and palate (an opening or gap in the upper lip and underlying bony palate) and burdened with the extensive physical rehabilitation as well as psychological and financial cost. Despite its impact, relatively little known about the contributing factors, both genetic and environmental, that predispose the fetus to this deformity. Our studies will shed some of the first light on the developmental mechanisms that are perturbed in affected individuals and thus ultimately aid future studies aimed at reducing the incidence of facial clefts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE018456-01A2
Application #
7580436
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2008-12-01
Project End
2012-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
1
Fiscal Year
2009
Total Cost
$371,520
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Rolfe, S M; Shapiro, L G; Cox, T C et al. (2011) A landmark-free framework for the detection and description of shape differences in embryos. Conf Proc IEEE Eng Med Biol Soc 2011:5153-6