Role of Fog2 in Lung and Diaphragm Development

描述（由申请人提供）： 肺发育不良伴发发育性肺功能缺陷导致高死亡率和发病率。 肺发育不全和肺发育不全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，我们鉴定了一种小鼠品系，其具有继发于Fog 2突变的异常乳房肌化和肺发育不全。 Fog 2基因敲除小鼠的肺发育不全，副叶发育不全。 我们在一名出生后第一天就因严重肺发育不全和肺发育缺陷而死亡的婴儿中发现了一种新生FOG 2杂合子无义突变。 由于这项工作表明FOG 2是人类肺发育不全和肺发育不全的第一个已知原因，因此了解Fog 2促进正常肺发育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Fog 2在肌肉向膈肌迁移中的作用。 在目标2中，将通过对Fog 2缺失小鼠的早期胚胎肺外植体中的分支基因的时空分析来探索Fog 2缺失导致副叶发育不全的机制。在目标3中，将对患有先天性乳房缺陷和肺发育不全的患者中的人基因FOG 2和加塔4/5/6进行测序。 候选人是一名儿科重症监护医师，对与先天性腹股沟疝（CDH）相关的腹股沟和肺部病变的发病机制感兴趣。 她一直有成为一名医生科学家的长期兴趣，并寻求一个正式的，指导培训计划，以发展成为一名成功的独立调查员所需的技能。 她提出的培训计划包括指导和与遗传学，肺生物学和先天性腹股沟疝领域的成功领导者合作。她是一个很好的支持候选人谁将受益于临床科学家发展奖。

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.