Pediatric dysphagia-chronic difficulty with feeding and swallowing-is a serious complication in children with neurodevelopmental disorders. Dysphagia can be recognized in between 35% and 80% of newborns, infants and older children with neurodevelopmental disorders, and the incidence is currently increasing. The consequences of pediatric dysphagia include failure to gain weight, malnutrition, acute choking, food aspiration and naso-sinus, middle ear, and lung aspiration related infections including pneumonia. Current therapies aim at relieving symptoms or modifying food to ease difficulties; however, there are neither cures nor preventive strategies for pediatric dysphagia. The lack of new approaches reflects a lack of fundamental understanding of neural and oro-pharyngeal mechanisms that are disrupted in pediatric dysphagia, and their developmental causes. Our research program will provide this fundamental understanding by defining the pathology, developmental origins, and approaches for prevention of pediatric dysphagia. Our goal is to provide a new foundation for better diagnosis and therapy for dysphagia in a variety of neurodevelopmental disorders and new clinically tractable approaches for preventing or diminishing dysphagia. Achieving this goal is now possible because our group has established the first genetically defined, behaviorally and pathologically validated model of pediatric dysphagia. We have found that the LgDel mouse model of 22q11 Deletion Syndrome, a genetic deletion neurodevelopmental disorder in which at least 45% of affected children have pediatric dysphagia, accurately recapitulates key dysphagic features: LgDel mouse pups fail to gain weight, aspirate milk acutely, and have a high incidence of naso-sinus, middle ear, and lung inflammation and infection. We will now use this powerful research tool to determine contributions of disrupted brainstem neural circuits versus oro-pharyngeal mechanics to pediatric dysphagia (PROJECT 1), how the pathology of pediatric dysphagia arises during development of the embryonic hindbrain (PROJECT 2), and how neural circuit or oro-pharyngeal pathology can be prevented by restoring disrupted development to normal status via maternal nutrition (PROJECT 3). These three projects will be supported by a core for administration (CORE A), animal models and dysphagia pathology (CORE B), genomics and bioinformatics (CORE C), and microscopic imaging and analysis (CORE D). Our research team has established expertise in cellular neurobiology, neurophysiology, neuropharmacology, developmental biology, genetics and genomics. We will work closely with our clinical partners at Children's National Health System to maximize translation of our results to viable new therapies for children with dysphagia. Thus, we are uniquely positioned to undertake the first truly integrated biological mechanistic analysis of pediatric dysphagia. Our results will be transformative: they will define new diagnostic criteria, therapies, and prevention strategies to improve the vital capacity of feeding and swallowing in children with neurodevelopmental disorders.

Public Health Relevance

Pediatric dysphagia is a common and devastating complication, especially in children with neurodevelopmental disorders. The underlying pathology of pediatric dysphagia is not understood, its origins in development are unknown, and there are currently no effective cures or strategies for prevention. Our research program will provide this knowledge with a transformative integrated analysis of mechanisms that disrupt feeding and swallowing in neurodevelopmental disorders, how they arise during early embryonic development, and how they can be prevented for at-risk fetuses by managing maternal diet during pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD083157-03
Application #
9234411
Study Section
Pediatrics Subcommittee (CHHD-A)
Program Officer
Parisi, Melissa
Project Start
2015-03-16
Project End
2020-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$1,093,025
Indirect Cost
$343,554
Name
George Washington University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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