The Effect of Endoplasmic Reticulum and Reductive Stress on the Human Dermal Fibroblast Proteome

Dermal fibroblasts are responsible for the secretion of extracellular matrix (ECM) components that support the structural integrity of the skin. Alterations to the ECM have been implicated in many skin diseases including systemic sclerosis and fibrotic disorders, as well as wrinkle formation and wound healing in the aged phenotype. The endoplasmic reticulum (ER) is responsible for the production and quality control of secreted proteins, and perturbations to its correct function could therefore lead to aberrant ECM deposition from dermal fibroblasts. ER stress occurs when homeostasis of this organelle is imbalanced, which can be prompted by the effects of redox agents that disrupt the careful redox balance within the ER lumen. Previous research has often focused on the effects of oxidising agents that lead to oxidative stress within the cells, however little is known about the effects of reductants (and therefore reductive stress). Reductants are present in pollutants, depilatory creams and some cosmetics yet relatively little is known about their potential effects on the skin. This thesis aims to investigate the effect of reductive stress on dermal fibroblasts, looking first at signalling responses and then investigating changes that occur at the proteomic level. In the final chapter a comparison is made between the proteomic response to reductive stress by DTT and oxidative stress by UV-A radiation. The implications of these findings are discussed in the context of fibroblast functions in the skin.