Developmental mechanisms for pediatric dysphagia

小儿吞咽困难的发育机制

基本信息

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
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/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

项目摘要

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 22q11缺失综合征（22q11DS）患者存在喂养和吞咽困难，影响其营养状况，并增加因误吸和反流引起的鼻腔、中耳和呼吸道感染。这这些临床上重大困难的原因尚不清楚。使用基因精确的 LgDel 小鼠 22q11DS 模型具有相似的表型特征，我们发现视黄酸介导的前- 后脑的后部模式发生改变，控制进食和进食的一些脑神经也发生了变化。吞咽在发育早期就有异常的生长模式。这些观察结果表明，异常后脑运动和/或感觉神经元的发育导致颅脑网络功能障碍执行进食和吞咽所需的神经元。我们将检验减少的假设 22q11 基因剂量通过视黄酸 (RA) 破坏前后 (A-P) 后脑模式信号传导，从而重新指定脑干和/或神经嵴前体细胞，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，以评估过量的配体可用性、测量后脑 RA 反应以评估增强的 RA 敏感性，并确定其他模式的变化 LgDel 胚胎中的中心及其目标，其中前部 CN 受到损害，Tbx1+/- 它们所在的位置幸免于难，LgDel:Raldh2+/- 在那里他们被救了。识别如果发生突变则容易面临风险的基因胎儿吞咽困难，在具体目标 2 中，我们将比较 WT 胚胎后脑的转录组， RA 信号增强的 LgDel 胚胎，以及返回 WT 的 LgDel:Raldh2+/- 胚胎水平。最后，在具体目标 3 中，我们将描述位置、分子身份、频率、增殖、和/或前部与后部后脑运动神经元、中间神经元、迁移前和后部运动神经元的迁移能力 LgDel 胚胎中的迁移性神经嵴前体，其中前 CN 受到损害，Tbx1+/- 其中他们幸免于难，而LgDel:Raldh2+/-则让他们获救。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，并确定这些如何机制会导致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产后早期诊断的分子途径以及有针对性的治疗干预措施。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度有围产期喂养和吞咽困难风险的胎儿的病理学。