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Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia

小儿吞咽困难的病理学、发育起源和预防

基本信息

批准号：
9234411
负责人：
ANTHONY S LAMANTIA
金额：
$ 121.45万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-16 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234411
关键词：
22q11 Deletion Syndrome Acute Address Affect Animal Model Anterior Aspirate substance Attention deficit hyperactivity disorder Autistic Disorder Behavioral Bioinformatics Biological Birth Brain Stem Cell physiology Cells Cellular Neurobiology Cellular biology Characteristics Child Childhood Choking Chronic Clinical Clinical Management Clinical assessments Collaborations Complication Cranial Nerves Data Deglutition Deglutition Disorders Development Developmental Biology Diagnosis Diet Dietary intake Embryo Embryonic Development Failure Fetal Growth Fetal Viability Folic Acid Food Foundations Functional disorder Gene Expression Regulation Genes Genetic Genetic Models Genetic Transcription Genomics Goals Growth Health Health system Image Analysis Incidence Infection Knowledge Lung Lung Inflammation Malnutrition Mechanics Micronutrients Milk Modeling Molecular Monitor Morphogenesis Mus Muscle Neurodevelopmental Disorder Neuropharmacology Newborn Infant Oropharyngeal Pathogenesis Pathologic Pathology Patients Pattern Peripheral Pharmacology Phenotype Physiological Pneumonia Positioning Attribute Pregnancy Prevention Prevention approach Prevention strategy Quality of life Research Resources Role Sinus Structure Symptoms Syndrome Testing Therapeutic Translations Tretinoin Vital capacity Weight Gain Work at-risk pregnancies craniofacial effective therapy experimental study feeding fetus at risk genetic analysis hindbrain improved insight intercellular communication interdisciplinary approach microdeletion microscopic imaging middle ear mother nutrition mouse model mutant neural circuit neurophysiology new therapeutic target novel diagnostics novel strategies novel therapeutics prenatal prevent programs prophylactic public health relevance pup reduce symptoms relating to nervous system tool

项目摘要

DESCRIPTION (provided by applicant): 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.