Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia

 描述(申请人提供)：儿童吞咽困难-慢性进食和吞咽困难-是神经发育障碍儿童的严重并发症。在患有神经发育障碍的新生儿、婴儿和年龄较大的儿童中，吞咽困难的发生率在35%到80%之间，目前这一比例正在上升。儿童吞咽困难的后果包括体重无法增加、营养不良、急性窒息、食物吸入和鼻窦、中耳以及与肺吸入有关的感染，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，对于儿童吞咽困难，既没有治愈方法，也没有预防策略。缺乏新的治疗方法反映了对儿童吞咽困难的神经和口咽机制及其发育原因缺乏基本的了解。我们的研究计划将通过定义儿童吞咽困难的病理、发育起源和预防方法来提供这一基本理解。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上易于处理的方法。实现这一目标现在是可能的，因为我们的团队已经建立了第一个经基因定义、行为和病理验证的儿童吞咽困难模型。我们发现，22q11缺失综合征的LgDel小鼠模型准确地概括了关键的吞咽障碍特征：LgDel小鼠幼鼠体重无法增加，吸奶困难，鼻窦、中耳、肺部炎症和感染的发生率较高。22q11缺失综合征是一种遗传缺失性神经发育障碍，至少45%的儿童有儿童吞咽困难。我们现在将使用这一强大的研究工具来确定脑干神经回路中断与口咽力学对儿童吞咽困难的贡献(项目1)，儿童吞咽困难的病理如何在胚胎后脑的发育过程中出现(项目2)，以及如何通过通过母体营养将中断的发育恢复到正常状态来预防神经回路或口咽病变(项目3)。这三个项目将得到管理核心(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(核心C)以及显微成像和分析(核心D)的支持。我们的研究团队已经在细胞神经生物学、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针对吞咽困难儿童的可行的新疗法。因此，我们处于独特的地位，可以进行第一个真正完整的儿科吞咽困难的生物机制分析。我们的结果将是变革性的：它们将定义新的诊断标准、治疗和预防战略，以改善患有神经发育障碍的儿童的进食和吞咽的肺活量。

 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.