Systems modelling age-related changes in the maintenance of dermal extra-cellular matrix: mechanisms and interventions.

皮肤结构的与皮肤病相关的变化，如变薄、起皱和弹性丧失，是真皮细胞外基质（ECM）的调节和组成变化的结果。随着年龄的增长，ECM的降解过程往往超过再生过程。其后果是我们都知道的可见变化，以及牛皮癣、纤维化、黑色素瘤和伤口愈合受损等疾病的发病率增加。针对这些变化背后的因果机制的高级抗衰老护肤产品是一个数十亿磅产业，预计在未来几十年内将继续增长。然而，关于这些机制仍有许多未知之处，深入了解ECM维持过程将提供更优质的产品，也许更重要的是，进一步了解皮肤老化过程本身。在护肤产品开发中使用动物是普遍的，但由于与人类在生物学上的根本差异，不一定是非常有用的。1998年，在英国销售的化妆品中首次禁止进行动物试验，2009年，欧盟在2013年扩大到所有国家。然而，许多动物，特别是实验室小鼠，通常用于基础研究，从而鉴定用于皮肤保健的新产品。在这里，我们的目标是使用一种系统生物学方法，将计算机发现和体外验证相结合，为动物实验提供一种强大的替代方案。我们将使用这种方法来生成与人类真皮中ECM维持相关的年龄变化的计算机模型，并使用它们来确定干预策略以应对不良变化。我们的计算模型将被告知从人类真皮细胞产生的数据，从而避免关注可能只在动物模型中相关的过程。一旦建立，计算机模型将被用于探索治疗策略，并在更复杂的组合，可以单独在实验室实验中进行。那些看起来很有希望的治疗方法将在我们的体外系统中进行测试，我们已经开发出非常像人类皮肤的系统。我们的体外真皮模型使我们能够密切控制哪些细胞在组织内生长以及我们如何研究它们。我们将使用我们的系统来帮助简化行业的产品开发。另一个成果将是一个中央计算资源，我们的数据和模型将被保存在一起，以及一个软件接口，允许其他人与模型进行交互。

Age-related changes to the structure of the skin such as thinning, wrinkling and loss in flexibility are the result of changes in the regulation and composition of the dermal extra-cellular matrix (ECM). With age processes that degrade the ECM tend to dominate over regenerative processes. The consequences are the visible changes we all know together with increased incidence of conditions such as psoriasis, fibrosis, melanoma and impaired wound healing. Advanced anti-ageing skin-care products that target the causal mechanisms underlying these changes are a multi-billion pound industry which is forecast to increase over the coming decades. However much remains unknown about these mechanisms, and an in depth understanding of the processes involved in the maintenance of the ECM will provide better quality products and - perhaps more importantly - further our understanding of the skin ageing process itself. The use of animals in skincare product development is widespread but is not necessarily very informative due to fundamental differences in biology with humans. Animal testing in cosmetics sold in the UK was first banned for tests carried out in the UK in 1998, EU in 2009 and extended to all countries in 2013. However, many animals, laboratory mice in particular, are routinely used in the basic research leading to identification of novel products for skin healthcare. Here, we aim to use a systems biology approach integrating in-silico discovery and in-vitro validation to offer a powerful alternative to animal experimentation. We will use this approach to generate computer models of age-related changes in the maintenance of ECM in the human dermis and use them to identify intervention strategies to counter undesirable changes. Our computational models will be informed with data generated from human dermal cells, thereby avoiding focus on processes that may only be relevant in animal models. Once established the computer models will be used to explore treatment strategies and in more complex combinations that can be carried out solely in laboratory experiments. Those treatments that look promising will be tested in our in-vitro system which we have developed to behave very much like human skin. Our in-vitro dermal model allow us close control over which cells are grown within the tissue and how we can study them. We will use our system to help streamline product development for industry. An additional outcome will be a central computational resource where our data and models will be kept together and a software interface to allow others to interact with the models.