GENETIC AND DEVELOPMENTAL MECHANISMS OF CONGENITAL DIAPHRAGMATIC HERNIA

项目总结 肺和肺血管系统的正常发育及其对出生的生理适应是 对所有新生儿的生存至关重要。一组患者患有异常的肺部和 肺血管发育是指婴儿出生时患有先天性横隔疝(CDH)。鼎晖是其中之一 所有先天畸形中最常见和最严重的，每3500名活产儿中就有一名 死亡率为20-50%。CDH患者的横隔膜上有一个洞，允许腹部器官 在胎儿发育过程中突出入胸腔。因此，这些组织中的肺和肺血管 由于胎儿胸腔缺乏足够的空间，患者往往发育不全。除了这种缺乏 太空中，我们最近的数据表明，导致横隔膜发育异常的基因缺陷 In患者还会导致肺和肺血管系统的异常发育。这些肺固有的 缺陷导致肺发育不全和肺动脉高压，这是死亡和长期死亡的主要原因。 慢性萎缩性脑病患者的长期发病率。肺的发生发育机制 CDH患者的发育不良和肺动脉高压尚不清楚。此外，目前 CDH的治疗是非特异性的，不会出现潜在的遗传和发育缺陷 把每个病人都考虑进去。我们的总体假设是CDH患者的遗传缺陷起着核心作用。 导致肺发育不全和肺动脉高压的机制。我们相信，通过确定 与CDH相关的肺发育和生理功能异常的内在机制，我们将 发现新的更具体的治疗方法。我们提出的实验将解决这一假设。 通过确定在CDH患者中发现突变的两个关键转录调节因子所起的作用， Pbx1和SIN3A。我们建议的目的是解决导致肺的每一种潜在机制。 发育不全和肺动脉高压包括：肺和肺的胚胎发育异常 血管系统，肺血管对出生的生理适应失败，以及出生后肺和 肺血管发育。在目标1中，我们关注Pbx1在出生后肺发育中所起的作用 和肺血管对出生的生理适应。在目标2中，我们重点关注SIN3A在 控制肺、血管和血管平滑肌的胚胎肺和肺血管发育 细胞增殖和分化。在这两个目标中，我们将确定下游的遗传和分子缺陷 由Pbx1或Sin3a功能丧失引起，并确定这些遗传缺陷是如何导致 肺的生理功能和肺血管系统。我们的实验结果将为 为未来针对特定潜在疾病的CDH患者的治疗干预奠定基础 这种疾病的机制。

PROJECT SUMMARY Normal development of the lungs and pulmonary vasculature, and their physiological adaptation to birth, is essential for the survival of all newborn infants. One group of patients who suffer from abnormal lung and pulmonary vascular development are infants born with congenital diaphragmatic hernia (CDH). CDH is among the most common and severe of all congenital malformations with a frequency of 1 in 3500 live births and a mortality rate of 20-50%. Patients with CDH have a hole in the diaphragm allowing the abdominal organs to herniate into the chest during fetal development. As a result, the lungs and pulmonary vasculature in these patients are often underdeveloped due to a lack of sufficient space in the fetal thorax. In addition to this lack of space, our recent data demonstrate that the genetic defects responsible for abnormal diaphragm development in patients also cause abnormal development of the lungs and pulmonary vasculature. These lung-intrinsic defects result in lung hypoplasia and pulmonary hypertension that are the major cause of mortality and long- term morbidity in patients with CDH. The genetic and developmental mechanisms responsible for lung hypoplasia and pulmonary hypertension in patients with CDH are not yet understood. Furthermore, current therapies for CDH are non-specific and do not take the underlying genetic and developmental defects unique to each patient into account. Our overall hypothesis is that genetic defects in patients with CDH play a central role in the mechanisms responsible for lung hypoplasia and pulmonary hypertension. We believe that by identifying the lung-intrinsic mechanisms of abnormal development and physiological function associated with CDH, we will uncover new and more specific approaches for treatment. Our proposed experiments will address this hypothesis by determining the roles played by two key transcriptional regulators found to be mutated in patients with CDH, PBX1 and SIN3A. The Aims of our proposal address each of the underlying mechanisms responsible for lung hypoplasia and pulmonary hypertension including: abnormal embryonic development of the lungs and pulmonary vasculature, failure of pulmonary vascular physiological adaptation to birth, and failure of postnatal lung and pulmonary vascular development. In Aim 1 we focus on the role played by Pbx1 in postnatal lung development and pulmonary vascular physiological adaptation to birth. In Aim 2 we focus on the role played by Sin3a in embryonic lung and pulmonary vascular development by controlling lung, vascular, and vascular smooth muscle cell proliferation and differentiation. In both Aims we will identify the downstream genetic and molecular defects caused by loss-of-function of Pbx1 or Sin3a and determine how these genetic defects cause impaired physiological function of the lungs and pulmonary vasculature. The results of our experiments will lay the groundwork for future therapeutic interventions for patients with CDH that target the specific underlying mechanisms of the disease.