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.

描述（由申请人提供）：小儿吞咽困难（慢性喂养和吞咽困难）是患有神经发育障碍的儿童的严重并发症，35% 至 80% 的患有神经发育障碍的新生儿、婴儿和年龄较大的儿童会出现吞咽困难。目前，儿童吞咽困难的发病率正在增加，其后果包括体重增加不足、营养不良、急性窒息、食物误吸和鼻窦炎。目前的治疗方法旨在缓解症状或改变饮食以缓解困难；然而，缺乏新方法反映了对神经和吞咽困难的基本了解。我们的研究项目将通过定义儿科吞咽困难的病理学、发育起源和预防方法来提供这一基本认识。我们的目标是为更好地预防儿科吞咽困难提供新的基础。诊断各种神经发育障碍的吞咽困难的治疗和预防或减少吞咽困难的新的临床治疗方法现在是可能实现的，因为我们的小组已经建立了第一个经过基因定义、行为和病理学验证的儿童吞咽困难模型。 22q11 缺失综合征的 LgDel 小鼠模型，这是一种基因缺失神经发育障碍，至少 45% 的受影响儿童患有小儿吞咽困难，准确地说概括了吞咽困难的关键特征：LgDel 小鼠幼崽体重增加困难、吸奶剧烈，并且鼻窦、中耳和肺部炎症和感染的发生率很高，我们现在将使用这一强大的研究工具来确定脑干受损的影响。神经回路与口咽力学对儿科吞咽困难的影响（项目 1），儿科吞咽困难的病理学是如何在胚胎后脑发育过程中产生的（项目2），以及如何通过母体营养将受损的发育恢复到正常状态来预防神经回路或口咽病理（项目3）这三个项目将得到管理核心（CORE A）、动物模型和吞咽困难的支持。我们的研究团队在细胞神经生物学、神经生理学、神经药理学、病理学（CORE B）、基因组学和生物信息学（CORE C）以及显微成像和分析（CORE D）方面建立了专业知识。我们将与国家儿童卫生系统的临床合作伙伴密切合作，最大限度地将我们的研究成果转化为针对吞咽困难儿童的可行新疗法。因此，我们处于独特的地位，可以进行第一个真正的综合生物机制分析。我们的研究结果将具有变革性：它们将定义新的诊断标准、治疗方法和预防策略，以提高患有神经发育障碍的儿童的喂养和吞咽的肺活量。