Developmental mechanisms for pediatric dysphagia

摘要 22q11排便综合征(22q11DS)患者进食和吞咽困难，影响他们的 营养状况，并增加鼻腔、中耳和呼吸道感染，因吸入和反流。这个 这些临床上显著困难的原因尚不清楚。使用遗传上准确的LgDel小鼠 具有相似表型特征的22q11DS模型，我们发现维甲酸介导的前房- 后脑的后脑模式被改变，控制摄食和 吞咽在发育早期就有异常的生长模式。这些观察表明，反常 后脑运动和/或感觉神经元发育导致脑神经网络功能障碍 执行摄食和吞咽所需的神经元。我们将检验这一假设。 22q11基因剂量通过维甲酸(RA)破坏前-后脑(A-P)模式 信号，从而重新指定脑干和/或神经脊前体细胞，导致吞咽困难。 我们在特定目标1中的实验将量化RA的产生，以评估过剩的配体可用性，测量 后脑RA反应以评估增强的RA敏感性，并确定附加图案的变化 前中枢神经系统受损的LgDel胚胎中的中心及其靶点，Tbx1+/-它们所在的位置 幸免于难，和LgDel：Raldh2+/-他们在那里获救。以确定如果突变，易患风险的基因 胎儿吞咽困难，在特定目标2中，我们将比较WT胚胎后脑的转录， RA信号增强的LgDel胚胎和返回WT的LgDel：Raldh2+/-胚胎 级别。最后，在特定目标3中，我们将描述位置、分子同一性、频率、增殖性 和/或后脑运动神经元、中间神经元、迁移前和 前中枢受损的LgDel胚胎中的迁移神经脊前体，其中Tbx1+/- 他们幸免于难，他们在LgDel：Raldh2+/-获救。项目2的结果将确立 项目1定义的儿童吞咽困难病理的发育性起源，并确定这些 这些机制导致了进食和吞咽中断的特定方面。我们的数据将定义新的 胎儿和出生后早期诊断的分子途径，以及有针对性的治疗干预。 项目3中的实验将评估这些目标在纠正吞咽困难关键方面的精确度。 有围产期喂养和吞咽困难风险的胎儿的病理学。

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.