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Thesis Research Summary:
Cutaneous wound healing is a complex process that is vitally important in restoring the dermal barrier and preventing further infection. However, repair does not always proceed smoothly. Previous studies have documented that the elderly do not heal as well as the young. As skin ages, functional properties associated with its dermal connective tissue begin to deteriorate. In skin, protein cross-linking is associated with the age-related loss in elasticity, increased stiffening and wrinkling. Although many factors contribute to these age-associated complications, our lab plans to investigate two precursors for advanced glycation end products (AGEs); 3-deoxyglucosone (3DG) and methylglyoxal (MG). Dermal fibroblasts are an essential component in synthesizing and maintaining the extracellular matrix (ECM), which is composed of collagens. Additionally, they can communicate with each other and other cell types. Fibroblasts regulate skin physiology and play a critical role in wound healing. Degradation of glycated proteins causes the formation of highly reactive species 3DG and MG, which in turn form AGEs. Both 3DG and MG play a role in the modification and cross-linking of long-lived proteins such as collagen. AGEs are found to accumulate on collagen and increase in number as a function of age and diet. It has been shown that AGEs modify the ECM, the action of hormones, the inflammatory response, and the signaling from the ECM to gene expression in fibroblasts via the ERK pathway.
We have shown that inhibition of 3DG by Dyn15 induces an increase in procollagen and in proliferation of fibroblasts. Thus, we have identified a potential therapy for chronic wounds. With the aging population growing in number and percentage, the need to understand the underlying mechanisms of age-related complications in wound healing has increased. By understanding the effects of 3DG and MG on fibroblast proliferation and signaling, and collagen expression we hope to yield important clues about the regulation of ERK during aging.
It is important to not only understand the role of 3DG and MG in the context of age but also in the context of gender. Independent of age, sex hormones can manifest a variety of biological and immunological effects in the skin. Estrogen appears to upregulate collagen expression and proliferation of fibroblasts, while testosterone appears to do the opposite. Elderly males are known to heal wounds more slowly than females, and with an enhanced inflammatory response, prompting the suggestion that circulating sex hormones may contribute to wound healing independent of age and diet. With emerging news of the benefits from hormone replacement therapy (HRT), it is important to understand the modulatory effects of estrogen and testosterone on the expression of AGEs, and the signaling from the ECM to gene expression within fibroblasts. |