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：
9567053
负责人：
ANTHONY S LAMANTIA
金额：
$ 15.95万
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/9567053
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.

描述（由适用提供）：喂养和吞咽的小儿吞咽困难 - 奇妙的难度 - 对于神经发育障碍儿童而言是严重的并发症。在35％至80％的新生儿，婴儿和年龄较大的神经发育障碍儿童中，吞咽困难可以被识别出来，目前这一事件正在增加。小儿吞咽困难的后果包括无法增加体重，营养不良，急性窒息，食物吸入和鼻音，中耳和肺抽吸相关感染，包括肺炎。当前的疗法旨在缓解症状或修饰食物以减轻困难；但是，既没有治疗方法，也没有针对小儿吞咽困难的预防策略。缺乏新方法反映出对小儿吞咽困难及其发育原因的神经和咽咽机制缺乏基本理解。我们的研究计划将通过定义病理学，发展起源和预防儿科吞咽困难的方法来提供这种基本的理解。我们的目标是为各种神经发育疾病的吞咽困难和吞咽困难的诊断和治疗提供新的基础，并为预防或减轻吞咽困难而采用新的临床上可行的方法。现在可以实现这一目标是可能的，因为我们的小组已经建立了第一个在行为和病理上验证的小儿刺激模型的遗传学定义。 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 dysphagiic features: LgDel mouse pups fail to gain weight, aspirate milk acutely, and have a high incidence of naso-sinus, middle ear, and lung infection and infection.现在，我们将使用这种强大的研究工具来确定破坏的脑干神经回路的贡献与脑咽部机制对小儿吞咽困难（项目1），小儿吞咽困难的病理如何通过在胚胎后脑的发展过程中产生小儿吞咽困难的病理学（项目2），以及通过材料或植物范围的水平来抑制材料或植物的病理学，从而阻止了材料或植物的病理学，从而可以在材料或phare脑识别的情况下进行病理学范围。（项目3）。这三个项目将得到给药的核心（核心A），动物模型和吞咽困难病理学（核心B），基因组学和生物信息学（Core C）以及显微镜成像和分析（核心D）。我们的研究团队在细胞神经生物学，神经生理学，神经药理，发育生物学，遗传学和基因组学方面建立了专业知识。我们将与儿童国家卫生系统的临床合作伙伴紧密合作，以最大程度地将结果转化为吞咽困难儿童的可行新疗法。因此，我们的位置是对小儿吞咽困难的第一个真正综合的生物学机械分析。我们的结果将具有变革性：他们将定义新的诊断标准，疗法和预防策略，以提高神经发育障碍儿童的喂养和吞咽能力。