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

皮肤老化是一个普遍的问题。基底膜将皮肤中的角质形成细胞（含有角蛋白的细胞）与结缔组织层分开。在衰老过程中，皮肤变薄与基底膜胶原（BMC）减少和皮肤屏障受损有关。皮肤屏障在保护皮肤免受外部伤害（如感染）方面很重要。我们发现BMC的丧失与角质形成细胞和细胞核中含有脱氧核糖核酸（DNA）的细胞骨架的变化之间存在联系。目的和目标：在第一个目标中，学生将设计角质形成细胞，使其失去BMC胶原。然后，我们可以研究BMC胶原蛋白的损失如何影响细胞分裂等过程，以及细胞如何在体外3D培养中形成皮肤。我们还可以描述皮肤屏障的特征。在第二个目标中，学生将使用机械拉伸或紫外线辐射对目标1中生成的3D培养物进行压力，以了解这如何影响核的形状以及核内部结构和过程，例如对压力的代谢反应。在第三个目标中，将使用一种技术来观察细胞核中蛋白质和DNA之间的相互作用，试图识别可能调节皮肤屏障发育的基因，这些基因会因BMC的丧失而改变。研究结果将在年轻和老化的皮肤中得到证实，以表明我们的结果与衰老有关。最后，在联合利华，学生将使用计算工具来识别可能用于逆转BMC丧失对皮肤屏障和正常皮肤稳态影响的化合物。这些化合物可以用于实验室老化的皮肤模型。潜在的应用和好处：这项工作将有助于了解正常的皮肤老化以及如何改善皮肤老化。这不仅与人类变老后的样子有关，还与预防皮肤感染和更好的伤口愈合有关。这可能会导致新的面霜的开发，以逆转皮肤老化或保持年轻的外观。

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.