Developmental mechanisms for pediatric dysphagia

小儿吞咽困难的发育机制

• 批准号: 9567059
• 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/9567059
• 关键词: 22q11; 22q11 Deletion Syndrome; Afferent Neurons; Anterior; Behavior; Birth; Brain Stem; Cephalic; Childhood; Cranial Nerves; Data; Deglutition; Deglutition Disorders; Development; Diagnosis; Diagnostic Procedure; Disease; Dysmorphology; Early Intervention; Embryo; Embryonic Development; Equilibrium; Experimental Designs; Folic Acid; Foundations; Frequencies; Gene Dosage; Genes; Growth; Interneurons; Ligands; Measures; Mediating; Molecular; Motor Neurons; Mus; Mutate; Neural Crest; Neurodevelopmental Disability; Neurons; Newborn Infant; Nose; Nutritional status; Oropharyngeal; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Perinatal; Phenotype; Positioning Attribute; Prevention; Prevention strategy; Process; Production; Publishing; Reflux; Respiratory Tract Infections; Signal Transduction; Specific qualifier value; Structure; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Tretinoin; clinically significant; ear infection; experimental study; feeding; fetal; fetus at risk; hindbrain; middle ear; mind control; mother nutrition; mouse model; neonate; nerve stem cell; network dysfunction; neural circuit; neurodevelopment; novel; postnatal; precursor cell; pup; response; targeted treatment; transcriptome

ABSTRACT 22q11Deletion Syndrome (22q11DS) patients have feeding and swallowing difficulties that compromise their nutritional status and increase nasal, middle ear, and respiratory infections due to aspiration and reflux. The causes of these clinically significant difficulties are unknown. Using the genetically accurate LgDel mouse model of 22q11DS, which has similar phenotypic features, we found that retinoic acid-mediated anterior- posterior patterning of the hindbrain is altered, and that several of the cranial nerves that control feeding and swallowing have aberrant growth patterns early in development. These observations suggest that aberrant development of the hindbrain motor and/or sensory neurons leads to dysfunction of the network of cranial neurons that are needed to execute feeding and swallowing. We will test the hypothesis that diminished 22q11 gene dosage disrupts anterior-posterior (A-P) hindbrain patterning via retinoic acid (RA) signaling, and thereby re-specifies brainstem and/or neural crest precursor cells, leading to dysphagia. Our experiments in Specific Aim 1 will quantify RA production to assess excess ligand availability, measure hindbrain RA responses to evaluate enhanced RA sensitivity, and determine changes of additional patterning centers and their targets in LgDel embryos where anterior CNs are compromised, Tbx1+/- where they are spared, and LgDel:Raldh2+/- where they are rescued. To identify genes that, if mutated, predispose at-risk fetuses to dysphagia, in Specific Aim 2 we will compare transcriptomes from the hindbrains of WT embryos, LgDel embryos in which RA signaling is enhanced, and LgDel:Raldh2+/- embryos in which it is returned to WT levels. Finally, in Specific Aim 3 we will characterize position, molecular identity, frequency, proliferative, and/or migratory capacities of anterior versus posterior hindbrain motor neuron, interneuron, pre-migratory and migratory neural crest precursors in LgDel embryos in which anterior CNs are compromised, Tbx1+/- in which they are spared, and LgDel:Raldh2+/- in which they are rescued. The results of PROJECT 2 will establish the developmental origins of pediatric dysphagia pathology defined by PROJECT 1, and determine how these mechanisms contribute to specific aspects of disrupted feeding and swallowing. Our data will define new molecular pathways for fetal and early postnatal diagnosis, and targeted therapeutic interventions. Experiments in PROJECT 3 will evaluate the precision of these targets for correcting key aspects of dysphagia pathology in fetuses at risk for perinatal feeding and swallowing difficulties.

抽象的 22Q11DETESTION综合征（22Q11DS）患者患有喂养和吞咽困难，损害了他们 营养状况并增加由于抽吸和反流而增加鼻，中耳和呼吸道感染。这 这些临床上严重困难的原因是未知的。使用遗传准确的LGDEL小鼠 具有相似表型特征的22q11ds的模型，我们发现视黄酸介导的前 - 后脑的后构图发生了改变，并且控制喂养和的几种颅神经 吞咽在开发初期具有异常的增长模式。这些观察表明异常 后脑电机和/或感觉神经元的开发导致颅内网络功能障碍 执行进食和吞咽所需的神经元。我们将测试减少的假设 22q11基因剂量破坏了通过视黄酸（RA）的前后（A-P）后脑模式 信号传导，从而重新指定脑干和/或神经rest前体细胞，导致吞咽困难。 我们在特定目标1中的实验将量化RA产量以评估过量配体可用性，测量 后脑RA的反应以评估增强的RA灵敏度，并确定其他图案的变化 前中枢神经系统受损的LGDEL胚胎中的中心及其目标，TBX1 +/- 幸免于LGDEL：RALDH2 +/-他们被救出的地方。鉴定基因，如果突变，易感性高危 胎儿到吞咽困难，在特定的目标2中，我们将比较来自WT胚胎后方的转录组， LGDEL胚胎增强了RA信号，LGDEL：RALDH2 +/-胚胎将其返回到WT 水平。最后，在特定目标3中，我们将表征位置，分子身份，频率，增殖， 和/或前后后脑运动神经元的迁徙能力，Interneuron，迁移前和迁徙能力 LGDEL胚胎中CNS的LGDEL胚胎中的迁移神经rest前体，TBX1 +/-其中 他们幸免，lgdel：raldh2 +/-被救出。项目2的结果将确定 项目1定义的小儿吞咽困难病理学的发育起源，并确定这些病理 机制有助于干扰喂养和吞咽的特定方面。我们的数据将定义新的 用于胎儿和早期产后诊断的分子途径，以及针对性的治疗干预措施。 项目3中的实验将评估这些目标的精度，以纠正吞咽困难的关键方面 胎儿的病理，面临围产期喂养和吞咽困难的风险。