ONTOGENY OF THE PERMEABILITY BARRIER

渗透屏障的个体发育

• 批准号: 2403282
• 负责人: MARY L WILLIAMS
• 金额: $ 22.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-15 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2403282
• 关键词: HMG coA reductases; acetyl coA carboxylase; acyltransferase; athymic mouse; body water dehydration; cholesterol; embryo /fetus; enzyme activity; epidermal growth factor; fatty acid synthase; glucocorticoids; histogenesis; hormone regulation /control mechanism; human fetus tissue; human tissue; laboratory rat; lipid biosynthesis; lovastatin; membrane permeability; messenger RNA; pulmonary surfactants; skin; sphingolipids; thyroid hormones; tissue /cell culture

Immaturity of the skin barrier is a major source of morbidity and mortality of the premature infant, yet little is known about mammalian permeability ontogenesis and its developmental regulation. In this proposal, approaches and insights derived recently from two investigative areas, i.e., the dynamic regulation of barrier maintenance in mature epidermis, and the hormonal regulation of lung surfactant maturation, will be utilized: 1) to define critical steps in barrier ontogenesis; 2) to identify physiologic and/or pharmacologic modifiers of its development; and 3) to characterize the mechanism(s) whereby they regulate barrier ontogenesis. The contribution of lipids synthesized within the epidermis will be assessed by determining the activity, content and mRNA levels of the key regulatory enzymes of barrier lipid synthesis (i.e., HMG CoA reductase, acetyl CoA carboxylase/fatty acid synthetase and serine palmitoyl transferase) during ontogenesis in the fetal rat. The requirement for specific lipids during barrier ontogenesis will be assessed utilizing specific inhibitors of cholesterol (ovastatin), fatty acid (TOFA) and sphingolipid (beta,chloroalanine) synthesis. The ability of selected hormones (i.e., glucocorticoids and thyroid hormone) and growth factors (EGF) to accelerate barrier maturation, as determined both morphologically (by nile-red histochemistry and electromicroscopy of osmium and ruthenium-tetroxide fixed tissue) and functionally (by measurement of transepidermal water loss) will be determined both in the fetal rat model and in human fetal skin, in organ culture and engrafted to nude mice. The mechanisms whereby effective agents accelerate barrier maturation will be determined by examining their effects on barrier lipid (cholesterol, fatty acid, sphingolipid_ content and synthesis; and on the activity, concentration and mRNA levels of their key regulatory enzymes. Delineation of the critical components required for development of barrier competence and physiologic and/or pharmacologic modifiers of its development may lead to new types of treatment for barrier immaturity (e.g., barrier lipid replacement and/or pharmacologic acceleration of barrier maturation).

皮肤屏障的不成熟是发病率和死亡率的主要来源 早产儿，但很少有人知道哺乳动物的渗透性 个体发生及其发育调控。 在这一建议中，方法 以及最近从两个调查领域得出的见解，即，的 在成熟表皮中屏障维持的动态调节，以及 将利用肺表面活性物质成熟的激素调节：1） 定义屏障个体发生的关键步骤; 2）识别生理性 和/或其发展的药理学修饰剂;和3）表征 它们调节屏障个体发育的机制。 的 表皮内合成的脂质的贡献将通过 确定关键调节因子的活性、含量和mRNA水平， 屏障脂质合成酶（即，HMG CoA还原酶，乙酰CoA 羧化酶/脂肪酸合成酶和丝氨酸棕榈酰转移酶） 胚胎大鼠的个体发育。 期间对特定脂质的需求 屏障个体发生将利用以下特异性抑制剂进行评估： 胆固醇（奥伐他汀）、脂肪酸（TOFA）和鞘脂 (beta氯丙氨酸）合成。 选择的激素的能力（即， 糖皮质激素和甲状腺激素）和生长因子（EGF），以加速 屏障成熟，如形态学上（通过尼罗红 锇和四氧化二锇组织化学和电镜观察 固定组织）和功能（通过测量经表皮水 损失）将在胎鼠模型和人胎鼠模型中测定。 皮肤，在器官培养和移植到裸鼠。 这些机制 加速屏障成熟有效试剂将通过 检查它们对屏障脂质（胆固醇，脂肪酸， 鞘脂含量和合成;以及对活性、浓度和 它们的关键调节酶的mRNA水平。 关键的描述 屏障能力和生理功能发展所需的成分 和/或其发展的药理学修饰剂可能导致新类型的 屏障未成熟的处理（例如，屏障脂质替代和/或 屏障成熟的药理学加速）。