Interaction of Genotype and Dietary Vitamin A in Cleft Lip and/or Palate

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 DESCRIPTION (provided by applicant): Clefting of the lip and/or palate (CL/P) is the most common facial birth defect. This disruption of normal facial structure can lead to difficulties wit necessary functions such as breathing, feeding, and speech development. Clinical manifestations of CL/P are highly variable, indicating that the disorder is likely caused by a complex interaction of genetic and environmental factors. There is currently great interest in identifying the environmental factors that interact with genetic susceptibility to effect clinical presentation of CL/P, as further understanding of these factors could lead to important new treatments and interventions. Maternal nutrition is both a known influence on craniofacial development and an ideal target for future interventions. This project will investigate how genotype and vitamin A levels in the maternal diet interact to influence midfacial development and CL/P susceptibility and severity. In the first aim of this project, a mouse model allowing precise control over bioavailable levels of vitamin A will be used to assess the impact of mild and moderate maternal vitamin A deficiency (VAD) on facial phenotype. Using deformable morphology analysis, difference in phenotypes will be quantified and are expected to reveal a graded degree of change in facial morphology corresponding to the degree of maternal VAD. The second aim of this project will use mouse models allowing dietary control of vitamin A and/or CL/P sensitivity to investigate the impact of mild and moderate maternal VAD and maternal vitamin A supplementation on CL/P severity and frequency. Severity of phenotypes will be quantified using deformable morphology methods. The results are expected to show an increase in cleft severity and frequency corresponding to the degree of maternal VAD and a protective effect associated with vitamin A supplementation. This work will further the understanding of the underlying mechanisms and environmental modulators contributing to CL/P susceptibility and sensitivity which will help identify optimal treatment and preventative strategies.