How does ageing related loss of basement membrane collagen regulate epidermal barrier homeostasis

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Skin ageing is a universal problem. The basement membrane separates the keratinocytes (which are cells containing keratin) in the skin from the connective tissue layer. During ageing, skin thinning is associated with decreased basement membrane collagens (BMC) and an impaired skin barrier. The skin barrier is important in protecting the skin from external insults such as infection. We have found a link between loss of BMC and changes to the cytoskeleton of the keratinocyte and the nucleus which contains deoxyribonucleic acid (DNA). Aims and Objectives:In the first objective, the student will engineer keratinocytes to have loss of BMC collagen. We can then study how loss of BMC collagen affects processes like cell division and how the cells form skin in vitro in 3D cultures. We can also characterize the skin barrier. In the 2nd objective, the student will stress the 3D cultures generated in objective 1 using mechanical stretch or ultraviolet radiation, to see how this affects the shape of the nucleus and the nuclear internal structures and processes such as metabolic responses to stress. In the 3rd objective, a technique will be used to look at interactions between proteins and DNA in the nucleus to try and identify genes that might be regulating skin barrier development that are altered by loss of BMC. Findings will be confirmed in young and ageing skin to show that our results are relevant to ageing. Finally, at Unilever the student will use computational tools to identify compounds that might be used to reverse the effects of loss of BMC on the skin barrier and normal skin homeostasis. These compounds can then be used on ageing skin models in the laboratory. Potential applications and benefits:This work should give insights into normal skin ageing and how it could be improved. This is relevant to not just how humans look as they get older, but also to prevention of skin infection and better wound healing. It could result in development of new creams to reverse skin ageing or maintain a youthful appearance.