Proper function of skin as a protective barrier depends on the successful completion of the terminal differentiation program. During the wound healing process, a series of events are observed in order to re- establish the barrier function of the skin. Immediately after a wound, the skin responds by producing an inflammatory response, followed by synthesis of new connective tissue, epithelial repopulation to close the wound and scar-remodeling. This complex process requires interactions between different cell types that must be temporally and spatially coordinated. The phenotype of caspase-8 conditional knockout mice share a similarity with the wound healing process in that there is an increased signal leading to the rapid proliferation of stem cells to close the wound. Under the auspices of this training fellowship, the following specific aims will be pursued: 1. Develop mouse models to determine whether caspase-8 regulates epidermal development and repair 2. Test whether caspase-8 ablation links epidermal hyperproliferation and inflammation 3. Isolate factors from cultured caspase-8 KO keratinocytes that lead to increased proliferation of keratinocytes during wound healing. One the most notable characteristic of stem cells and the reason there is much hope for these cells to be used to combat disease is their capacity to proliferate. In a cancerous growth, this property is also seen but the signals that regulate this process have gone awry. Moreover, many characteristics of wounding such as inflammation and alterations in tissue microenvironment are contributing factors of cancer progression. Therefore, knowledge of factors that stimulate stem cells to proliferate is vital to our ability to counterattack these cells. The potential of a secreted factor from the outer layer of the epidermis signaling deeper into the skin to activate stem cell division would likewise provide an accessible target to combat cancers of the skin.
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