The skin serves as a protective barrier, which limits water loss and prevents penetration of allergens, irritants and pathogens into the body. A disturbance of the epidermal barrier is involved in the pathogenesis of a variety of major skin diseases, including ichthyosis, psoriasis and atopic dermatitis. In recent years the analysis of the pathomechanisms underlying these diseases, including barrier function alterations, have been studied in patients and in mouse models.
Much less attention is paid to rare diseases with epidermal barrier defects. One of the most severe rare diseases is the Netherton Syndrome, with a prevalence of 1.35 per 100.000. In Netherton Syndrome patients, mutations in the so-called Spink5 gene lead to overactivation of proteases, which are responsible for epidermal desquamation. The consequence is the detachment of the most upper layers of the epidermis, which constitute a major part of the epidermal barrier. This leads to an epidermal barrier break-down, which then allows the penetration of allergens, irritants and/or pathogens. This and other mechanisms stimulate inflammation and allergic reactions, which can be life threatening in severe cases of Netherton Syndrome.
We recently showed that genetic and pharmacological activation of the cytoprotective transcription factor Nrf2 in keratinocytes enhances expression of a protein, which blocks proteases responsible for epidermal desquamation. Furthermore, Nrf2 activation increased the levels of proteins and lipids, which constitute the epidermal barrier.
Therefore, in the proposed project, we want to investigate whether genetic or pharmacological activation of Nrf2 and consequent upregulation of these and other factors ameliorates the phenotypic abnormalities in a mouse model of Netherton Syndrome and in other mice with defects in the epidermal barrier. Studies with cultured keratinocytes from Netherton Syndrome patients will complement this work. Together, the proposed experiments will provide the basis for the development of novel compounds for the treatment of Netherton Syndrome patients and other patients with a defective barrier. Through collaboration with clinical experts, we will be able to transfer our results into clinical practice. Our long-term goal is the development of a novel and efficient therapy for Netherton Syndrome.
Was ist das Besondere an diesem Projekt?
Current therapeutic strategies to re-establish a functional barrier in Netherton Syndrome patients are rather inefficient and unspecific. Therefore, there is a strong need for development of improved and targeted therapies.
Previous findings from our lab and others suggest that activation of Nrf2 could be a powerful strategy to reduce barrier function impairments resulting from different epidermal abnormalities. In the proposed project we want to determine if activation of NRF2 induces compensatory pathways in the skin of Netherton Syndrome patients. This will provide the basis for a clinical trial to determine the usefulness of topical application of pharmacological NRF2 activators in Netherton Syndrome patients. This is particularly promising, since NRF2-activating compounds are in clinical trials for prevention of other diseases, and thus our proposed strategy has the potential of rapid clinical applicability.
Hovnanian, A. 2013. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 351:289-300;
Huebner, A.J., Dai, D., Morasso, M., Schmidt, E.E., Schafer, M., Werner, S., and Roop, D.R. 2012. Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero. Developmental cell 23:1238-1246;
Schäfer, M., Dutsch, S., auf dem Keller, U., Navid, F., Schwarz, A., Johnson, D.A., Johnson, J.A., and Werner, S. 2010. Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis. Genes & development 24:1045-1058;
Schäfer, M., Farwanah, H., Willrodt, A.H., Huebner, A.J., Sandhoff, K., Roop, D., Hohl, D., Bloch, W., and Werner, S. 2012. Nrf2 links epidermal barrier function with antioxidant defense. EMBO molecular medicine 4:364-379.
None so far
Am Projekt beteiligte Personen
Letzte Aktualisierung dieser Projektdarstellung 17.10.2018