Changes in epidermal function are critically important in the pathogenesis of wound healing complications that occur in ageing skin. A better understanding of how keratinocyte interactions with the cutaneous extracellular matrix are altered in ageing skin is essential to understanding mechanisms that underlie age-related defects in wound healing. Integrin a3b1 is an extracellular matrix receptor for laminin-332 that is expressed in the basal cell layer of the epidermis and is upregulated during wound healing. Previous studies from our lab have shown that a3b1 is a critical regulator of keratinocyte migration and wound reepithelialization. In addition, our recent data suggest a distinct and completely novel role for a3b1 in inducing expression of pro-angiogenic factors in keratinocytes, whereby it may mediate cross-talk between the epidermis and endothelial cells that promotes wound angiogenesis. These findings suggest that a3b1 expression in epidermis is important for two distinct and fundamental aspects of cutaneous wound healing, reepithelialization and angiogenesis, both of which are reduced in ageing skin and may contribute to impaired wound healing in the elderly. Therefore, a3b1 is an excellent candidate for mediating epidermal wound healing functions that diminish with age, and it provides a likely target for therapeutic approaches aimed at improving wound healing in the elderly. In the proposed research, we will combine a murine model of ageing skin with epidermis-specific a3 knockout to test if reduced a3b1 expression in the epidermis predisposes skin to wound healing defects, and to test if specific a3b1 functions in the epidermis that facilitate wound healing are altered in aged skin. In order to characterize the molecular mechanisms involved, these in vivo approaches will be complemented by cell culture studies to identify a3b1-dependent functions in keratinocytes that change as a function of age. This work should enhance our understanding of how integrin-mediated epidermal responses to ECM change during intrinsic ageing and whether these changes contribute to reduced wound healing in aged skin, and it may reveal new therapeutic targets for wound treatment in elderly patients.
A key to the development of therapies to facilitate cutaneous wound healing in the elderly is the identification of molecular mechanisms that control wound repair, and an understanding of how those mechanisms change in aging skin. The proposed studies will identify novel roles for integrins of the epidermis in regulating keratinocyte migration and angiogenesis during wound healing, and will explore whether age-related changes in these functions contribute to impaired wound healing in aging skin. These pathways may be exploitable as therapeutic targets to facilitate wound repair in elderly patients.
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