Untersuchungen zur biologischen Rolle von neuen Kazal-typ Inhibitoren LEKTI-2 und LEKTI-3

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Analyses of healthy skin stratum corneum for antimicrobial peptides led to the discovery of two novel „lympho-epithelial Kazal-Type” protease inhibitors (LEKTI-2 and LEKTI-3). Whereas recombinant LEKTI-2 has antimicrobial properties and is a selective inhibitor of Kallikrein 5 (KLK-5), recombinant LEKTI-3 lacks antimicrobial activity, but exhibits potent inhibitory activities against both, tryptic KLK5 and chymotryptic KLK7. These two proteases have an essential role in the epidermal desquamation, which is disturbed in Netherton-Syndrome, an inflammatory skin disease with disrupted skin barrier due to a LEKTI-1 gene defect that causes LEKTI-1 deficiency. This was proven in LEKTI-1 k.o.- mice, which show a phenotype resembling Netherton syndrome patients.To study whether both novel LEKTIs are of similar importance in desquamation, LEKTI-2- und later also LEKTI-3 knock-out mice as well as transgenic mice overexpressing these LEKTIs will be generated. In this cooperation project in my laboratory murine LEKTI-2- and -3 orthologs will be cloned, its tissue expression in mice analysed and then recombinantly expressed for analyses of antimicrobial and protease-inhibiting properties, in particular for inhibition of desquamation-relevant kallikreins. We will further generate mLEKTI-2 and -3-antibodies for immunohistochemistry and ELISAs for LEKTI-2- and 3- to analyse its role in desquamation of various mouse models.