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).
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