NEW PRENATAL THERAPY FOR CONGENITAL DIAPHRAGMATIC HERNIA

先天性膈疝的新产前治疗

• 批准号: 2445002
• 负责人: JAY J SCHNITZER
• 金额: $ 8.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445002
• 关键词: apoptosis; congenital disorders; developmental genetics; diaphragm; disease /disorder model; embryo /fetus pharmacology; embryo /fetus tissue /cell culture; embryology; endothelin; gene expression; gene targeting; genetic enhancer element; gestational age; glucocorticoids; hernia; hormone therapy; immunocytochemistry; laboratory rat; messenger RNA; nitric oxide synthase; organ culture; polymerase chain reaction; pulmonary surfactants; sheep; subtraction hybridization

The condition of CDH occurs when the diaphragmatic muscle, which separates the chest from the abdomen, falls to form completely in the developing fetus. The intestines, no longer confined to the abdomen, herniate into the thorax. The defect is often associated with immaturity of the lungs; it is not a rare condition, affecting nearly one in 2,000 pregnancies. Despite many major advances in the surgery and intensive care of infants with CDH, the mortality from the malformation remains as high as 60%. The infants die from inadequate lung function, which is a combination of 1) pulmonary hypoplasia and 2) persistent pulmonary hypertension of the newborn. Lungs of full term infants with CDH are similar to lungs of premature infants. We have used the nitrofen-induced model of CDH in the fetal rat to demonstrate that the lungs are immature by biochemical, morphometric, physiologic, and molecular biologic criteria. We have shown further that the lethally immature lungs of the full term CDH rats can be improved by treating the mothers with parenteral glucocorticoids at doses extrapolated from the current therapy used to accelerate lung development of premature human babies. Addition of thyroid hormone augments this effect. We will search for more potent pulmonary growth enhancers at the gene level, evaluate expression of developmentally regulated genes in CDH, and investigate the role of apoptosis in CDH. We have developed an in vitro organ culture system of nitrofen-induced pulmonary hypoplasia using quantitative mathematical and fractal techniques to screen new agents; we will test their efficacy and optimize dosing in the rat model, then extend these experiments to fetal sheep in whom CDH has been surgically, rather than pharmacologically, created. Combination of these systems will allow us to pretest and develop appropriate therapies for CDH that can be used in future clinical trials for prenatal treatment of humans in whom CDH has been detected in utero by ultrasound.

CDH 的情况发生在膈肌分离时 胸部从腹部，在发育中完全下降形成 胎儿。肠道不再局限于腹部，而是疝入 胸部。这种缺陷通常与肺部发育不成熟有关。 这并不是一种罕见的情况，影响近二千分之一的怀孕。 尽管在婴儿手术和重症监护方面取得了许多重大进展 CDH 的畸形死亡率仍高达 60%。这 婴儿死于肺功能不足，这是 1) 的组合 肺发育不全和2）持续性肺动脉高压 新生。患有 CDH 的足月婴儿的肺部与正常婴儿的肺部相似 早产儿。我们使用除草醚诱导的 CDH 模型 胎鼠通过生化证明肺未成熟， 形态测量、生理学和分子生物学标准。我们已经展示了 此外，足月 CDH 大鼠致命的未成熟肺可以 通过按剂量注射肠外糖皮质激素治疗母亲可得到改善 从目前用于加速肺部发育的疗法推断 早产儿。添加甲状腺激素可以增强这种作用 影响。我们将寻找更有效的肺部生长促进剂 基因水平，评估CDH中发育调控基因的表达， 并研究细胞凋亡在CDH中的作用。我们开发了一种在 除草醚诱导的肺发育不全的体外器官培养系统 定量数学和分形技术来筛选新药物；我们 将在大鼠模型中测试其功效并优化剂量，然后扩展 这些实验是针对经过 CDH 手术的胎儿羊进行的，而不是 比药理学上创造的。这些系统的组合将允许 我们预先测试并开发可用于 CDH 的适当疗法 未来对 CDH 患者进行产前治疗的临床试验 是在子宫内通过超声波检测到的。