Med Sys Chronic Wounds work package 3 project 1
Table of Contents
Identification of gene regulatory networks involved in the transition between proliferation and differentiation of kerationcytes
The cutaneous response to injury and stress comprises a temporary, tightly controlled change in the balance between epidermal proliferation and differentiation. To define the underlying gene regulatory network dynamics, which control a keratinocyte´s decision to enter the terminal differentiation program, we will generate time-resolved microarray data from keratinocytes, which were driven into differentiation via different methods (e.g. shift of calcium concentration, conditioned medium from mesenchymal cells, specific chemokines). Analysis of these data by methods of system biology enables us to establish an in silico model of keratinocyte differentiation (collaboration: Busch/Eils/Grabe – WP1). This will allow predictions on the possible regulatory function of currently unknown hub-proteins or pathways critical for the initiation of keratinocyte differentiation. In order to further improve this model, we will perform several rounds of refinement by functional analyses (gain-of-function and loss-of-function approaches) of individual proteins of interest. Taken together, these results will enable us to gain deeper insight into the cellular principles and regulatory networks controlling the differentiation process. Importantly, these studies may allow to predict ontime-dependent combinatory application of external factors initiating distinct signalling pathways inside the cell, by which the decision of the keratinocytes can be manipulated. Finally, we will transfer the insights to a preclinical situation: the pro-regeneratory effects of the combinatory treatment will be studied in an in vivo wound healing model (collaboration: G. Germann – WP5).
