ONTOGENY OF THE PERMEABILITY BARRIER

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DESCRIPTION: (Adapted from the applicant's abstract) - With improved survival of the premature infant, immaturity of the stratum corneum (SC) with an incompetent cutaneous barrier has become a major source of morbidity. The investigator has recently shown that ligands of several receptors in the nuclear receptor superfamily (for example, glucocorticoids, thyroid hormone) are important regulators of fetal SC development. However, because SC development proceeds normally in fetal skin organ cultures in the absence of hormones and in vivo in the face of glucocorticoid or thyroid hormone deficiency the applicants hypothesized that fetal SC development may also be activated by locally generated ligands of nuclear hormone receptors. Recently, they have shown that activators of PPARalpha (activator-fatty acids) or FXR (activator-farnesol, an isoprenoid derived from intermediates in the cholesterol biosynthetic pathway) accelerate fetal epidermal and SC development. Fetal epidermis is a very active site of both fatty acid and cholesterol synthesis, and therefore both of these nuclear hormone receptor ligands/activators are produced locally and thereby could modulate SC development. Both PPARalpha and FXR are members of the RXR subgroup of nuclear hormones receptors which also includes RXR, RAR, and Vitamin D receptor. Given the important regulatory role of nuclear receptors in the skin it is likely that both PPARalpha and FXR will also have crucial roles in epidermal physiology. Hypothesis: Formation of the SC and a competent barrier during fetal development requires both the generation of extracellular lipid-enriched lamellar membranes and the cornified envelope, both of which are regulated by activation of PPARalpha and/or FXR nuclear receptors. Specific Aims: 1) To determine if PPARalpha and FXR activators accelerate SC development in utero and following premature birth. 2) To elucidate the basis for the acceleration of SC ontogenesis the investigators will determine if PPARalpha and/or FXR activators increase the expression and/or activity of key enzymes and structural proteins required for SC formation. 3) To determine if PPARalpha and/or FXR are the crucial signaling proteins that regulate the timetable of development of the SC/permeability barrier.