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).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD029706-01A2
Application #
2202088
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1994-05-15
Project End
1998-04-30
Budget Start
1994-05-15
Budget End
1995-04-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Feingold, Kenneth R; Moser, Arthur; Shigenaga, Judy K et al. (2014) Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages. J Lipid Res 55:2501-8
Feingold, Kenneth R; Shigenaga, Judy K; Kazemi, Mahmood R et al. (2012) Mechanisms of triglyceride accumulation in activated macrophages. J Leukoc Biol 92:829-39
Feingold, Kenneth R; Grunfeld, Carl; Heuer, Josef G et al. (2012) FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis. Endocrinology 153:2689-700
Feingold, Kenneth R; Shigenaga, Judy K; Cross, Andrew S et al. (2012) Angiopoietin like protein 4 expression is decreased in activated macrophages. Biochem Biophys Res Commun 421:612-5
Feingold, Kenneth R; Moser, Arthur; Shigenaga, Judy K et al. (2011) Inflammation inhibits GPR81 expression in adipose tissue. Inflamm Res 60:991-5
Feingold, Kenneth R; Shigenaga, Judy K; Patzek, Sophie M et al. (2011) Endotoxin, zymosan, and cytokines decrease the expression of the transcription factor, carbohydrate response element binding protein, and its target genes. Innate Immun 17:174-82
Hachem, Jean-Pierre; Roelandt, Truus; Schürer, Nanna et al. (2010) Acute acidification of stratum corneum membrane domains using polyhydroxyl acids improves lipid processing and inhibits degradation of corneodesmosomes. J Invest Dermatol 130:500-10
Lu, Biao; Moser, Arthur; Shigenaga, Judy K et al. (2010) The acute phase response stimulates the expression of angiopoietin like protein 4. Biochem Biophys Res Commun 391:1737-41
Feingold, Kenneth R; Kazemi, Mahmood R; Magra, Amy L et al. (2010) ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists. Atherosclerosis 209:81-8
Fluhr, Joachim W; Elias, Peter M; Man, Mao-Qiang et al. (2010) Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? J Invest Dermatol 130:2141-4

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