Med Sys Chronic Wounds work package 3 project 2
Table of Contents
The role of JNK in cutaneous wound healing
During maintenance of epithelial thickness or regeneration after wounding epidermal keratinocytes require a delicate balance between proliferation, migration and differentiation. The decision to enter either one of the genetic programs controlling these processes is regulated by both intra- and intercellular regulatory networks, the latter ones being mediated by soluble factors such as cytokines and growth factors. Intercellular communications initiate intracellular signal transduction pathways and, at their receiving end, a program of specific target genes regulating the status of the recipient cells.
We have drawn our attention to fibroblasts of the connective tissue as a source of soluble factors, particularly cytokines, acting in a trans-regulatory fashion to control epithelial cell behaviour. Previously, by employing an in vitro co-culture system composed of primary human keratinocytes and genetically modified mouse fibroblasts we have defined c-Jun/AP-1 regulated genes in fibroblasts, such as KGF, GM-CSF, SDF-1 and HGF, whose gene products affect keratinocyte proliferation and migration.
Using this co-culture system, we have recently observed that deficiency for the MAP kinase family member c-jun N-terminal kinase (JNK) in fibroblasts strongly affects the genetic program adjusting the balance of keratinocyte proliferation and differentiation. Thus, the present project is focusing on the signaling cascade downstream of the JNK, such as the identification of critical JNK substrates distinct from c-Jun. Moreover, novel target genes controlled by JNK activity, particularly growth factors and cytokines will be identified via acquisition and modeling of time-resolved microarray data (collaboration: Busch/Eils – WP1). Finally, cutaneous wound healing experiments will be performed using newly generated transgenic mouse models carrying a dermal-specific JNK1 deletion in the presence or absence of the second member of JNK protein family, JNK2. These experiments will define the importance of JNK function as well as JNK-regulated gene programs for skin homeostasis and wound healing.
