Role of Fog2 in Lung and Diaphragm Development

描述(由申请人提供)： 与发育性横隔膜缺陷相关的肺发育不良会导致高度的死亡率和发病率。横隔膜缺陷和肺发育不良的发病机制和发育关系尚不清楚。在对妊娠晚期胚胎的突变筛选中，我们发现了一种继发于Fog2突变的小鼠系，其横隔肌化和肺发育不良异常。Fog2基因缺失小鼠的肺发育不良，伴有副叶发育不全。我们在一名出生第一天死于严重肺发育不良和横隔膜缺陷的婴儿身上发现了一种新生的FOG2杂合子无义突变。由于这项工作表明FOG2是人类首个已知的横隔膜缺陷和肺发育不全的原因，了解Fog2促进正常横隔膜和肺发育的机制将为这些先天性缺陷的发病机制提供有价值的见解。在目标1中，将研究Fog2在肌肉向横隔膜迁移中的作用。目的2通过对Fog2基因缺失小鼠早期胚胎肺外植体分支基因的时空分析，探讨Fog2缺失导致副叶发育不全的机制。在目标3中，人类基因FOG2和GATA 4/5/6将在先天性膈肌缺陷和肺发育不全患者中进行测序。应聘者是一名儿科强化医师，对先天性横隔膜和先天性横隔膜疝气(CDH)相关的横隔膜和肺部病变的发病机制感兴趣。长期以来，她一直有成为一名内科科学家的兴趣，并寻求一个正式的、有指导的培训计划，以发展成为一名成功的独立研究员所需的技能。她提出的培训计划包括与遗传学、肺部生物学和先天性横隔膜疝气领域的成功领导者进行指导和合作。她是一位支持率很高的候选人，将从临床科学家发展奖中受益匪浅。

DESCRIPTION (provided by applicant): The pulmonary hypoplasia associated with developmental diaphragmatic defects causes a high degree of mortality and morbidity. The pathogenesis and developmental relationship between diaphragmatic defects and pulmonary hypoplasia is poorly understood. In a mutagenesis screen of late gestation embryos, we identified a mouse line with abnormal diaphragmatic muscularization and pulmonary hypoplasia secondary to a mutation in Fog2. Lungs from Fog2 null mice are hypoplastic with agenesis of the accessory lobe. We found a de novo FOG2 heterozygote nonsense mutation in a baby who died on the first day of life with severe pulmonary hypoplasia and a diaphragmatic defect. As this work demonstrates that FOG2 is the first known cause of diaphragmatic defect and pulmonary hypoplasia in the human, understanding the mechanisms by which Fog2 contributes to normal diaphragmatic and lung development will provide valuable insight into the pathogenesis of these congenital defects. In Aim 1, the role of Fog2 in muscle migration to the diaphragm will be studied. In Aim 2, the mechanism by which lack of Fog2 results in accessory lobe agenesis will be explored through temporal-spatial analysis of branching genes in early embryonic lung explants of Fog2 null mice. In Aim 3, the human genes, FOG2 and GATA 4/5/6 will be sequenced in patients with congenital diaphragmatic defects and pulmonary hypoplasia. The candidate is a pediatric intensivist with an interest in the pathogenesis of diaphragmatic and pulmonary lesions related to congenital diaphragmatic hernia (CDH). She has had a long standing interest in becoming a physician scientist and seeks a formal, mentored training program to develop the skills necessary to become a successful independent investigator. Her proposed training program includes mentorship and collaborations with successful leaders in the field of genetics, pulmonary biology, and congenital diaphragmatic hernia. She is a well supported candidate who will benefit highly from a Clinical Scientist Development Award.