Molecular Mechanisms of Neonatal Pulmonary Hemorrhage

新生儿肺出血的分子机制

• 批准号: 9565805
• 负责人: Hyung Joon Chun
• 金额: $ 54.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9565805
• 关键词: ANGPT2 gene; Air; Angiopoietin-2; Biological Assay; Birth; Blood; Blood Transfusion; Blood Vessels; Blood Volume; Blood flow; Cessation of life; Clinical; Complex; Complication; Data; Deposition; Development; Disease; Down-Regulation; Drops; Ductus Arteriosus; Endothelium; Etiology; Exposure to; Extracellular Matrix; Extravasation; Failure; Family; Frequencies; Genes; Genetic; Goals; Growth Factor; Hemorrhage; Homeostasis; Impairment; In Vitro; Infant; Investigation; Knockout Mice; Left; Lung; MAP Kinase Gene; MAPK7 gene; Mammals; Measures; Modeling; Molecular; Mus; Neonatal; Newborn Infant; Outcome; Oxygen; Patent Ductus Arteriosus; Pathogenesis; Pathway interactions; Permeability; Pharmacology; Phenotype; Phosphotransferases; Physiological; Prevention; Process; Production; Proteins; Pulmonary Circulation; Pulmonary Vascular Resistance; Pulmonary artery structure; Reporting; Respiratory Failure; Role; Secondary to; Series; Shunt Device; Signal Transduction; System; Testing; Therapeutic; Transgenes; Transgenic Mice; Vascular Endothelial Growth Factors; Ventilator; cadherin 5; conventional therapy; design; efficacy testing; experimental study; fetal; foramen ovale; hemodynamics; imaging modality; in vivo; knock-down; microCT; novel; novel therapeutic intervention; postnatal; premature; protein function; response; shear stress; spatiotemporal; surfactant; therapeutic target; transcription factor; vascular bed

Abstract The pulmonary vasculature is unique in that it is subjected to a remarkable change in hemodynamic forces immediately after birth. Increase in oxygen tension with the first breath results in decreased pulmonary vascular resistance, which in conjunction with closure of the ductus arteriosus and foramen ovale, leads to marked increase in the blood flow through the pulmonary blood vessels. While the majority of infants can respond to such a change in hemodynamic forces via vascular stabilization and maturation, those in whom complications occur can succumb to respiratory failure and death. Neonatal pulmonary hemorrhage (NPH) is such a complication occurring in about 1 in 1000 births. We hypothesize that failure of proper maturation of the pulmonary arteries, involving disruption of flow induced ERK5 activation, is a key mechanism of NPH. Currently NPH lacks any well-defined etiology and conventional therapy remains mainly supportive. We propose to test the hypothesis that excess production of the growth factor Angiopoietin 2 (ANGPT2) in the lung, which results from disrupted ERK5 signaling, is a key therapeutically targetable mechanism in infants with NPH. Using a combination of mouse genetic and pharmacologic models and in vitro studies, we propose to test the relevant role of the ERK5-ANGPT2 pathway in promoting stabilization of the pulmonary vasculature in the pivotal newborn period. Our ultimate goal will be to develop new therapeutic strategies for NPH, which may be applicable to other contexts of pulmonary vascular instability.

摘要 肺血管系统是独特的，因为它受到一个显着的变化，血液动力学 出生后立即生效。第一次呼吸时氧分压的增加导致 肺血管阻力，其与动脉导管的闭合以及 卵圆孔导致通过肺血管的血流显著增加。 虽然大多数婴儿可以通过血管扩张对血流动力学的这种变化做出反应， 稳定和成熟，发生并发症的患者可能死于呼吸衰竭 与死新生儿肺出血（NPH）是这样一种并发症，发生在约1 1000个新生儿我们假设肺动脉的成熟失败，包括 流动中断诱导的ERK 5活化是NPH的关键机制。目前，NPH缺乏 明确的病因和常规治疗仍然主要是支持性的。我们建议测试 假设在肺中过量产生生长因子血管生成素2（ANGPT 2）， ERK 5信号传导中断的结果，是婴儿中关键的治疗靶向机制， NPH。使用小鼠遗传和药理学模型以及体外研究的组合，我们 建议测试ERK 5-ANGPT 2通路在促进细胞稳定中的相关作用， 新生儿关键期的肺血管。我们的最终目标是开发新的 NPH的治疗策略，这可能适用于其他情况下的肺血管 不稳定