Grantee: Professor MSO Ulrich auf dem Keller, Department of Biotechnology and Biomedicine, Technical University of Denmark
Amount: DKK 2,603,579
Epidermal renewal and keratinocyte differentiation are pivotal for skin homeostasis and maintenance of the skin’s barrier function, which is impaired in inflammatory skin diseases.
Expression of dermokine, a member of the stratified epithelium secreted peptides complex, is highly upregulated under these conditions, but its functional contribution to epidermal stratification and differentiation remains largely elusive.
We have identified dermokine as a substrate of the wound- and tumor-related matrix metalloproteinase (MMP) 10 in vitro and in vivo, a proteolytic processing event that might play a role in maintaining the phenotype of transient amplifying keratinocytes in hyperproliferative epidermis.
In this project, we will characterize the activity of dermokine and analyze its putative function in keratinocyte differentiation. Using advanced proteomics, we will identify surface binding proteins for dermokine on keratinocytes. Newly identified dermokine-receptor interactions will be characterized and related to signaling pathways that are activated in response to dermokine binding.
To test the hypothesis that MMP10 modulates dermokine activity, we will analyze the full-length protein in comparison to a truncated mutant, resulting from MMP10 cleavage. This mutant will be characterized for altered effects on keratinocyte differentiation, binding to receptor candidates and activation of downstream signaling.
This study will provide insight into the function and mechanisms of action of dermokine in normal and hyperproliferative epithelia and add to current knowledge on MMPs as modulators of extracellular signaling ligands in the skin. Anticipated results will help to devise new strategies for therapeutic intervention with barrier defects in inflammatory skin diseases.