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

• 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
• 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

 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-慢性进食和吞咽困难-是神经发育障碍儿童的严重并发症。吞咽困难可以在35%至80%的新生儿、婴儿和患有神经发育障碍的较大儿童中被识别，并且目前发病率正在增加。小儿吞咽困难的后果包括体重增加失败、营养不良、急性窒息、食物吸入和鼻窦、中耳和肺吸入相关感染，包括肺炎。目前的治疗方法旨在缓解症状或改变食物以缓解困难;然而，儿科吞咽困难既没有治愈方法也没有预防策略。缺乏新的方法反映了缺乏对儿童吞咽困难的神经和口咽机制及其发育原因的基本理解。我们的研究计划将通过定义儿科吞咽困难的病理，发育起源和预防方法来提供这种基本的理解。我们的目标是为更好地诊断和治疗各种神经发育障碍中的吞咽困难提供新的基础，并为预防或减少吞咽困难提供新的临床易处理的方法。实现这一目标现在是可能的，因为我们的小组已经建立了第一个遗传定义，行为和病理学验证的儿科吞咽困难模型。我们发现，22 q11缺失综合征（一种遗传缺失神经发育障碍，其中至少45%的受影响儿童患有儿科吞咽困难）的LgDel小鼠模型准确地概括了关键的吞咽困难特征：LgDel小鼠幼崽无法增加体重，急性吸乳，并且具有较高的鼻窦，中耳和肺部炎症和感染的发生率。我们现在将使用这个强大的研究工具来确定中断的脑干神经回路与口咽力学对儿科吞咽困难的贡献（项目1），在胚胎后脑发育过程中如何出现儿科吞咽困难的病理（项目2），以及如何通过母体营养恢复中断的发育到正常状态来预防神经回路或口咽病理（项目3）。这三个项目将由管理核心（CORE A）、动物模型和吞咽困难病理学核心（CORE B）、基因组学和生物信息学核心（CORE C）以及显微成像和分析核心（CORE D）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、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密切合作，最大限度地将我们的结果转化为治疗吞咽困难儿童的可行新疗法。因此，我们处于独特的地位，进行第一次真正整合的儿科吞咽困难的生物机制分析。我们的研究结果将是变革性的：它们将定义新的诊断标准，治疗方法和预防策略，以提高神经发育障碍儿童的喂养和吞咽能力。