Molecular basis of epidermal barrier function

Erwin Schrödinger Fellowship J 1901 Molecular basis of epidermal barrier function Matthias SCHMUTH 06.03.2000 The skin as the interface between the human body and the environment has an important protective function against physical, chemical or biological external assaults. Epidermal barrier functios is located in the outermost sheath, of the skin, the stratum corneum consisting of protein-enriched corneocytes embedded in a continuous lipid-enriched intercellular matrix. These compartments derive from the tightly regulated process of epidermal differentiation. The protein versus lipid arms of keratinoryte differentiation of the underlying epidermis are traditionally viewed as concurrent, but independent prorcesses, with the extracellular lipids being essential for barrier function. Because recently impairment of barrier function has been observed in ichtyas s with protein defects, in this proposal the significance of the protein arm of epidermal differentiation will be teste by assessing the epidermal permeability barrier in hereditary skin disease with deletions (i.e. lamellar ichthyosis) or mutations, (i.e. epidermolytic hyperkeratosis) of corneocyte proteins in human disease and corresponding animal models. In a first set of experiments functional data of the permeability barrier will be obtained from the human and animal disease models. Based on these findings morphological (light-, electron-microscopy) and biochemical (protein-, lipis- analysis) data will be obtained. In a final step the barrier dedects will be simulated in vitro by overexpression/suppression of the respective proteins in keratinocyte culture. Since a permeability barrier abnormality could contribute to the pathophysiology of these disorders, ameloratiqn of the barrier abnormality should improve clinical symptomatology. Moreover, basic understanding of epidermal homeostasis and future therapeutic advances are dependent on the knowledge of the molecular mechanisms of barrier function, which should emerge from these studies.