Role of epidermal lipoxygenases in congenital ichthyoses: Molecular mechanisms of pathogenesis and development of novel therapeutic approaches

• Applicants: Dr. Peter Krieg; Professor Dr. Holm Schneider
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 191593660

The autosomal recessive congenital ichthyoses (ARCI) constitute a heterogeneous group of genodermatoses characterized by erythema and generalized scaling of the skin. Causative mutations in nine different genes have been reported, among which the lipoxygenase genes ALOX12B und ALOXE3 are frequently affected. ALOX12B und ALOXE3 encode the epidermal lipoxygenases 12R-LOX and eLOX-3, respectively, two closely linked enzymatic components of a still incompletely characterized metabolic pathway in the skin. Disruption of the 12R-LOX/eLOX-3 pathway results in a defective epidermal permeability barrier and an ichthyosiform phenotype both in patients and knockout mice. The overall aim of this project is the elucidation of molecular mechanisms of pathogenesis and the development of novel therapeutic approaches using mouse models with constitutive or conditional inactivation of LOX genes in the epidermis, artificial murine skin equivalents, and skin samples of human patients. 12R-LOX and eLOX-3 play a major role in the processing of acylceramides which are important structural components of the cutaneous barrier function. Lack of these protein-bound ceramides is the main reason for a defective permeability barrier. Our first objective, therefore, is an evaluation of pharmacological approaches to ceramide replacement on skin equivalents in vitro and in conditional knockout mouse models, aiming at a topical treatment option. LOX products released during ceramide processing are considered to be potent lipid mediators. Related epoxyalcohol derivatives of arachidonic acid, the hepoxilins A3 and B3, are further products of eLOX-3 activity that are formed during conversion of the 12S-LOX metabolite 12S-HPETE. We will try to explore, whether and to what extent these LOX products may act as signaling molecules both during normal skin differentiation and after loss of cutaneous barrier function. Third, we aim at an elucidation of the molecular signaling processes that lead to an ichthyosiform phenotype subsequent to loss of the permeability barrier. We will focus on the role of MAP kinase cascades in the transcriptional regulation of genes involved in the changes of keratinocyte proliferation and differentiation resulting from the barrier defect.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Dr. Alan Brash, Ph.D.
• Co-Investigator: Professorin Dr. Judith Fischer, Ph.D.