Studier av mutationer i keratiner och lipidmetaboliserande enzymer som påverkar hudbarriären: Ledtrådar till nya terapimöjligheter.

Tidsperiod: 2013-01-01 till 2015-12-31

Projektledare: Hans Törmä

Medarbetare: Anders Vahlquist, Rolf Larsson, Marie Virtanen

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 1 800 000 SEK

Genetic diseases affecting the skin barrier may seriously impair the patients´ quality of life and may even be lethal in the postnatal period. Common symptoms are wide-spread blistering or general scaling and erythema. Existing therapies are inadequate, especially regarding epidermolysis bullosa (EB) and congenital ichthyosis. In order to find new therapies for EB simplex (EBS) and epidermolytic ichthyosis (EI) caused by dominant-negative keratin mutations, we utilize patients? immortalized keratinocytes as disease models. Recently we showed a reduction of stress-induced pathognomonic keratin aggregates after exposing the cells to chemical chaperones. This will now be followed by a high-content screening of many other drug candidates, the best of which will be further tested in animal models of EBS and EI (supplied by colleagues in the USA). In another part of the project we will examine the pathogenic role of 6 genes underlying autosomal recessive congenital ichthyosis (ARCI) to test the hypothesis that various disturbances in epidermal lipid metabolism via a common pathway result in a barrier failure and a chronic repair mechanism. The expression and colocalization of the enzymes will be analyzed in patients´ skin and in vitro models of ARCI. Also, the formation of certain lipids important for the formation of the skin barrier will be studied by LC-MS. The results may clarify the cause of many genodermatoses and identify novel therapeutic options.