Role of Fog2 in Lung and Diaphragm Development

描述（由申请人提供）： 与发育性膈肌缺陷相关的肺发育不全导致高度的死亡率和发病率。 膈肌缺损和肺发育不全之间的发病机制和发育关系尚不清楚。 在妊娠晚期胚胎的诱变筛选中，我们发现了一个因 Fog2 突变继发的膈肌肌化异常和肺发育不全的小鼠系。 Fog2缺失小鼠的肺发育不良，副叶发育不全。 我们在一名婴儿中发现了新的 FOG2 杂合子无义突变，该婴儿在出生第一天就因严重肺发育不全和膈肌缺损而死亡。 由于这项工作表明 FOG2 是人类膈肌缺陷和肺发育不全的第一个已知原因，因此了解 Fog2 促进膈肌和肺正常​​发育的机制将为了解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 在肌肉迁移到膈肌中的作用。 在目标 2 中，将通过对 Fog2 缺失小鼠的早期胚胎肺外植体中的分支基因进行时空分析，探索 Fog2 缺乏导致副叶发育不全的机制。在目标 3 中，将对先天性膈肌缺陷和肺发育不全患者的人类基因 FOG2 和 GATA 4/5/6 进行测序。 该候选人是一名儿科重症监护医生，对与先天性膈疝 (CDH) 相关的膈肌和肺部病变的发病机制感兴趣。 她长期以来一直对成为一名医学科学家感兴趣，并寻求一个正式的、有指导的培训计划来培养成为一名成功的独立研究者所需的技能。 她提出的培训计划包括与遗传学、肺生物学和先天性膈疝领域的成功领导者进行指导和合作。她是一位备受支持的候选人，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.