| Summary: | The dynamics and complexity of tissue repair are dominated by specific and
intricately coordinated cellular events. Disruptions at the level of cellular
communication are associated with imbalanced extracellular matrix (ECM)
synthesis/degradation leading to fibrosis and chronic wounds. Our group has
demonstrated that 14-3-3 sigma (also known as stratifin) functions as a
stimulator of matrix metalloproteinase-1 (MMP-1) through interactions with
aminopeptidase N (APN) on the surface of dermal fibroblasts. In this doctoral
research project, it is hypothesized that APN functions as a receptor for
keratinocyte-derived paracrine signals that control the expression of key ECM
components in dermal fibroblasts.
Three specific objectives were accomplished in this project. Under Objective
1, the nature of APN expression in an environment of active epithelial-stromal
communication was examined using an in vitro keratinocyte-fibroblast crosstalk
model. The fibroblast expression of APN was significantly upregulated in the
presence of keratinocyte-releasable soluble factors, of which stratifin was shown
to be a potent stimulator. In light of the recent identification of APN as a receptor
responsible for stratifin-mediated p38 MAPK activation leading to upregulation of
MMP-1, the role of APN as a transmembrane mediator of signals that regulate
ECM remodeling was investigated in Objective 2. Comparative analysis of the
expression profiles of 118 ECM genes under conditions of keratinocyte
stimulation and APN gene silencing revealed a group of key matrix proteases
and adhesion molecules influenced by keratinocyte-derived signaling mediated through APN. The aim of Objective 3 was to explore the therapeutic potential of targeting APN in cutaneous tissue repair. Topical application of an APN-neutralizing antibody on full-thickness skin wounds in a murine model had a positive outcome in healing. Acceleration of wound closure was accompanied by increased collagen deposition and fibroblast contractility.
Collectively, the findings presented herein confirmed our hypothesis that APN can be induced by keratinocytes and acts as a regulator of keratinocyte-derived stimuli in epidermal-dermal communication. Specifically, these findings support the receptor role of APN in mediating transmembrane signals derived from keratinocytes, and provide encouraging evidence for further investigations on the therapeutic use of APN agonist/antagonists in the field of tissue repair. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate
|
|---|
