Generation and functional analysis of mouse models for two dominant human genodermatoses: Hydrotic Ectodermal Dysplasia (HED) and Keratitis-Ichthyosis-Deafness (KID)

• Antragsteller: Professor Dr. Klaus Willecke
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2006 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 31866643

Two targeted mouse models for dominant human genodermatoses will be generated that express human missense mutations in the highly homologous mouse genes: the connexin30 A88V mutation which causes hydrotic ectodermal dysplasia (HED) and the connexin26 S17F mutation which is responsible for the Keratitis-lchthyosis- Deafness (KID) syndrome in humans. Using these mouse models we want to explore the molecular mechanisms of these diseases which are characterized by phenotypic abnormalities in the epidermis (HED and KID) and, additionally, syndromic deafness (only KID). It is likely that the phenotypes caused by these dominant mutations in humans are due to the interaction of the mutated connexin proteins with other connexins expressed in keratinocytes of the epidermis. Thus, we shall explore these interactions in the epidermis of the anticipated transgenic mice but also in cultured cells which express these mutations after transfection. For this purpose we shall use a newly designed bidirectional vector with which pairs of connexins can be induced by doxycycline to about the same level of expression. We shall further study the intercellular spreading of microinjected tracer molecules in connexin transfected cultured cells and subsequently in acute skin slices from transgenic mice. In particular, we want to analyse inositol-1,4,5 trisphosphate (IP3) triggered Ca2+ spreading. In case of the KID mouse model we want to investigate in addition the hearing capability of these mice, the stability of the corresponding connexin proteins in the inner ear and the tracer transfer (including Ca2+ waves) in organotypic cochlear cultures.

• DFG-Verfahren: Sachbeihilfen