GENETIC AND DEVELOPMENTAL MECHANISMS OF CONGENITAL DIAPHRAGMATIC HERNIA

先天性膈疝的遗传和发育机制

• 批准号: 10426377
• 负责人: David J McCulley
• 金额: $ 39.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-17 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426377
• 关键词: Abdomen; Address; Affect; Alveolar; Birth; Blood Vessels; Blood capillaries; Cell Differentiation process; Cell Proliferation; Cells; ChIP-seq; Chest; Congenital Abnormality; Congenital diaphragmatic hernia; Data; Defect; Development; Disease; Elastin; Embryo; Embryonic Development; Failure; Fetal Development; Frequencies; Future; Genetic; Genetic Models; Genetic Transcription; Growth; Growth and Development function; Impairment; Infant Development; Live Birth; Lung; Mechanics; Mediator of activation protein; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle Tonus; Muscle relaxation phase; Mutant Strains Mice; Mutate; Mutation; Myofibroblast; Newborn Infant; Organ; Pathway interactions; Patients; Perinatal; Phenotype; Physiological; Physiological Adaptation; Physiology; Play; Pulmonary Hypertension; Regulatory Pathway; Respiratory Diaphragm; Respiratory Failure; Role; Severities; Testing; Therapeutic Intervention; Vascular Smooth Muscle; experimental study; fetal; improved; loss of function; lung development; mortality; mouse genetics; novel; novel strategies; postnatal; pulmonary function; transcriptome sequencing; vascular smooth muscle cell proliferation

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.

项目概要 肺和肺血管系统的正常发育及其对出生的生理适应是 对于所有新生儿的生存至关重要。一组患有肺部异常和 肺血管发育不良的婴儿出生时患有先天性膈疝（CDH）。 CDH位列其中 所有先天性畸形中最常见和最严重的一种，发生率为 3500 例活产儿中就有 1 例，并且 死亡率20-50%。 CDH 患者的膈肌上有一个孔，使腹部器官能够活动 胎儿发育时疝入胸腔。结果，这些区域的肺和肺血管系统 由于胎儿胸腔缺乏足够的空间，患者往往发育不全。除了这个不足之外 太空中，我们最近的数据表明，导致隔膜发育异常的遗传缺陷 患者的肺部和肺血管系统发育异常。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。 CDH 患者的足月发病率。肺的遗传和发育机制 CDH 患者的发育不全和肺动脉高压尚不清楚。此外，当前 CDH 的治疗方法是非特异性的，不考虑 CDH 特有的潜在遗传和发育缺陷。 考虑到每个患者。我们的总体假设是 CDH 患者的遗传缺陷起着核心作用 在导致肺发育不全和肺动脉高压的机制中。我们相信，通过识别 与 CDH 相关的肺发育异常和生理功能的内在机制，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个假设 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发挥的作用， PBX1 和 SIN3A。我们提案的目标是解决导致肺部疾病的每一个潜在机制 发育不全和肺动脉高压，包括：肺和肺的胚胎发育异常 脉管系统、肺血管对出生的生理适应失败以及出生后肺和功能衰竭 肺血管发育。在目标 1 中，我们重点关注 Pbx1 在出生后肺部发育中发挥的作用 以及肺血管对出生的生理适应。在目标 2 中，我们重点关注 Sin3a 在 通过控制肺、血管和血管平滑肌来促进胚胎肺和肺血管的发育 细胞增殖和分化。在这两个目标中，我们将识别下游遗传和分子缺陷 由 Pbx1 或 Sin3a 功能丧失引起，并确定这些遗传缺陷如何导致受损 肺和肺血管系统的生理功能。我们的实验结果将奠定 为未来针对特定基础疾病的 CDH 患者的治疗干预奠定基础 疾病的机制。