ANDROGEN BIOLOGY TO FETAL LUNG DEVELOPMENT

雄激素生物学对胎儿肺部发育的影响

• 批准号: 2807392
• 负责人: John Steven Torday
• 金额: $ 7.08万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2807392
• 关键词: androgens; chemoprevention; combination chemotherapy; disease /disorder model; glucocorticoids; hormone therapy; laboratory rabbit; messenger RNA; nonhuman therapy evaluation; progesterone; progestins; protein biosynthesis; pulmonary surfactants; respiratory disorder chemotherapy; respiratory distress syndrome of newborn

Respiratory distress syndrome (RDS), the leading cause of death and illness among premature infants, is due to pulmonary surfactant deficiency. Maternal glucocorticoid treatment, which stimulates fetal surfactant production, is the only preventive treatment for RDS. For unknown reasons, this therapy is only effective in about 50% of treated infants. Androgens in fetal circulation act as anti-glucocorticoids, inhibiting fetal lung maturation and pulmonary surfactant production. We have discovered that circulating fetal adrenal androgens are high in glucocorticoid-treated infants who develop RDS. We hypothesize that anti- androgens combined with glucocorticoids will be more effective than glucocorticoids alone for the prevention of RDS. Androgen-treated rabbit fetuses will be used as a model for persistent fetal adrenal androgen production to determine how androgens inhibit glucocorticoid-stimulated surfactant production in vivo. This model of androgen-inhibited surfactant production will be used to evaluate the ability of the natural anti- androgen progesterone to reverse the inhibition of glucocorticoid- stimulated surfactant production, since progestins can safely be used in human pregnancy. Progesterone analogs with varying degrees of anti- androgenic activity will systematically be evaluated in vitro and then in vivo. to develop the most rapid-acting, biologically effective anti- androgen to reverse the inhibitory actions of androgens on glucocorticoid- stimulated surfactant production. The anti-androgenic effects of these progestins will be compared with the potent anti-androgen Flutamide, which effectively reverses the androgen inhibition of glucocorticoid-stimulated surfactant production. The potential therapeutic benefits of the experimental hormone treatments will be determined by measuring the relative amounts of surfactant phospholipid and surfactant protein in fetal rabbit lung wash and tissue, and their rates of synthesis and mRNA expression. The effects of these experimental hormonal therapies on both glucocorticoid receptor mRNA expression and binding activity will also be evaluated, since this is a key regulator of hormone-dependent surfactant production. Since this receptor mechanism is common to all glucocorticoid- sensitive fetal organs, e.g. lung, brain, gut, heart, skin, our Long Term Goal is to develop a rapid, effective antenatal glucocorticoid therapy for all of these immature organs. The novel therapeutic approach represents a breakthrough in the clinical treatment for premature infants.

呼吸窘迫综合征（RDS）是导致死亡的主要原因， 早产儿中的疾病，是由于肺表面活性剂 缺陷母体糖皮质激素治疗，刺激胎儿 表面活性剂生产，是RDS的唯一预防性治疗。为 由于未知原因，这种疗法仅在约50%的治疗中有效。 婴儿。胎儿循环中的雄激素作为抗糖皮质激素， 抑制胎肺成熟和肺表面活性物质的产生。我们 已经发现循环中的胎儿肾上腺雄激素在 糖皮质激素治疗的婴儿发生RDS。我们假设反- 雄激素与糖皮质激素联合使用将比 糖皮质激素单独用于预防RDS。雄激素处理兔 胎儿将用作持续性胎儿肾上腺雄激素的模型 以确定雄激素如何抑制糖皮质激素刺激 在体内产生表面活性剂。这种雄激素抑制表面活性剂模型 生产将被用来评估能力的天然抗- 雄激素孕酮逆转糖皮质激素的抑制作用- 刺激表面活性剂的产生，因为孕激素可以安全地用于 人类怀孕具有不同程度抗- 雄激素活性将在体外进行系统评价，然后在 vivo.开发出最快速起效的生物学上最有效的抗 雄激素逆转雄激素对糖皮质激素的抑制作用， 刺激表面活性剂的产生。 这些药物的抗雄激素作用 孕激素将与强效抗雄激素的Fluoride进行比较，Fluoride 有效逆转糖皮质激素刺激的雄激素抑制 表面活性剂生产。潜在的治疗益处 实验性激素治疗将通过测量 表面活性剂磷脂和表面活性剂蛋白的相对量 胎兔肺洗液和组织，及其合成率和mRNA 表情这些实验性激素疗法对这两种疾病的影响 糖皮质激素受体mRNA的表达和结合活性也将是 评价，因为这是一个关键的调节剂依赖于表面活性剂 生产由于这种受体机制是所有糖皮质激素共同的- 敏感的胎儿器官，例如肺、脑、肠、心脏、皮肤、我们的长期 目的是开发一种快速，有效的产前糖皮质激素治疗， 所有这些未成熟的器官这种新的治疗方法代表了 早产儿临床治疗的突破。