Pediatric dysphagia, or difficulties with feeding and swallowing, is associated with many developmental disorders; however, the underlying causes remain poorly characterized. Consequently, at present there are no strategies to prevent feeding and swallowing defects. In this proposal, we will examine the potential of maternal nutrition during pregnancy to prevent pediatric dysphagia in the LgDel mouse model of 22q11 deletion syndrome (22q11DS). Our preliminary data suggest that pediatric dysphagia in newborn LgDel mice is due, at least in part, to abnormal development of the hindbrain and cranial nerves (CNs). Furthermore, we show that development of these structures in LgDel embryos is sensitive to exposure to the maternal dietary factor vitamin A (VA) and its active metabolite retinoic acid (RA). Thus, we will test the hypothesis that altered levels of vitamin A and other micronutrients in the maternal diet can prevent dysphagia by correcting underlying abnormal hindbrain, CN, and/or craniofacial development. To test this hypothesis, we will establish optimal protocols for modifying VA levels in the maternal diet to reduce the severity of pediatric dysphagia, identify the targets of altered RA exposure resulting in reduced phenotypic severity, and elucidate the molecular mechanisms that underlie this new prevention strategy.
In Specific Aim 1, we will define the relationship between maternal intake of VA and fetal RA levels. We will then ask if maternal exposures that are benign for WT animals correct key feeding and swallowing phenotypes in dysphagic postnatal LgDel pups.
In Specific Aim 2, we will define the developmental mechanisms, including those discovered in PROJECT 2, that are modulated by modified maternal VA intake. Thus we will better define the causal relationship between developmental disruption and feeding and swallowing difficulties.
In Specific Aim 3, we will investigate the effect of maternal nutrition on the expression or activity of 2 22q11DS candidate genes: Ranpb1 and Tbx1. We will characterize dysphagia-related phenotypes in Ranbp1 mutants, assess the interaction of this mutation with Tbx1, and determine the effect of altered VA/RA exposure. Together these experiments will define how developmental and molecular mechanisms underlying pediatric dysphagia during embryonic development can be exploited to prevent the disorder. Most importantly, these studies will provide a foundation for using an established strategy for optimal prenatal care?modified maternal nutrition?to prevent pediatric dysphagia in at risk pregnancies.

Public Health Relevance

There are currently no effective strategies for preventing the devastating consequences of pediatric dysphagia, especially in children with complex neurodevelopmental disorders. We will ask whether carefully managed maternal nutrition can prevent pediatric dysphagia in a mouse model of 22q11 Deletion Syndrome, and will define the developmental and molecular mechanisms by which maternal nutrition influences pediatric dysphagia. These experiments will result in strategies to prevent pediatric dysphagia in at-risk pregnancies?a safe and effective opportunity to substantially improve the health of children at risk for neurodevelopmental disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD-A)
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George Washington University
Domestic Higher Education
United States
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Wang, Xin; Bryan, Corey; LaMantia, Anthony-Samuel et al. (2017) Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome. Neuroscience 359:1-7
Karpinski, Beverly A; Bryan, Corey A; Paronett, Elizabeth M et al. (2016) A cellular and molecular mosaic establishes growth and differentiation states for cranial sensory neurons. Dev Biol 415:228-241
LaMantia, Anthony-Samuel; Moody, Sally A; Maynard, Thomas M et al. (2016) Hard to swallow: Developmental biological insights into pediatric dysphagia. Dev Biol 409:329-42
Baker, Jennifer L; Wood, Bernard; Karpinski, Beverly A et al. (2016) Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures. Gene Expr Patterns 20:71-9
Meechan, Daniel W; Maynard, Thomas M; Tucker, Eric S et al. (2015) Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development. Prog Neurobiol 130:1-28
Paronett, Elizabeth M; Meechan, Daniel W; Karpinski, Beverly A et al. (2015) Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation. Cereb Cortex 25:3977-93