NEW PRENATAL THERAPY FOR CONGENITAL DIAPHRAGMATIC HERNIA

先天性髋关节脱位的情况发生时， 胸部从腹部，福尔斯完全在发育中形成 胎儿肠不再局限于腹部，疝入 胸部这种缺陷通常与肺的不成熟有关; 这种情况并不罕见，每2,000名孕妇中就有一人受到影响。 尽管婴儿的外科手术和重症监护取得了许多重大进展， 对于CDH，畸形的死亡率仍然高达60%。的 婴儿死于肺功能不足，这是1） 肺发育不良和2）持续性肺动脉高压 新生儿患有CDH的足月婴儿的肺与 早产儿我们已经使用了除草醚诱导的CDH模型， 胎鼠以通过生化证明肺未成熟， 形态学、生理学和分子生物学标准。我们已经表明 此外，足月CDH大鼠的致死性未成熟肺可以 通过给母亲注射一定剂量的非肠道糖皮质激素 从目前用于加速肺部发育的疗法中推断 人类早产儿的死亡率甲状腺激素的补充增强了这一点 效果我们将寻找更有效的肺生长促进剂， 基因水平，评估CDH中发育调控基因的表达， 探讨细胞凋亡在CDH中的作用。我们开发了一种 除草醚诱导肺发育不良的体外器官培养系统 定量的数学和分形技术来筛选新的代理人，我们 将在大鼠模型中测试其功效并优化剂量，然后扩展 这些实验的胎儿羊，其中CDH已手术，而不是 ，创造，创造。这些系统的组合将允许 我们要预先测试和开发适当的治疗CDH， 在未来对患有CDH的人进行产前治疗的临床试验中 在子宫内被超声波检测到。

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.