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

与年龄相关的皮肤结构变化，如变薄、起皱和柔韧性丧失，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，退化的ECM倾向于主导再生过程。其后果是我们都知道的看得见的变化，以及诸如牛皮癣、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先进抗衰老护肤产品是一个价值数十亿英镑的产业，预计在未来几十年还会增长。然而，这些机制仍有很多未知之处，深入了解ECM维护过程将提供更高质量的产品，也许更重要的是，进一步了解皮肤老化过程本身。动物在护肤产品开发中的使用是广泛的，但不一定是非常有用的，因为生物学与人类的根本差异。1998年，英国首次禁止在化妆品中进行动物实验，2009年，欧盟禁止在化妆品中进行动物实验，并于2013年扩展到所有国家。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，我们的目标是使用系统生物学方法集成在硅发现和体外验证，以提供一个强大的替代动物实验。我们将使用这种方法生成人类真皮中ECM维持中与年龄相关的变化的计算机模型，并使用它们来确定干预策略以对抗不希望发生的变化。我们的计算模型将使用来自人类真皮细胞的数据，从而避免关注可能仅与动物模型相关的过程。一旦建立，计算机模型将用于探索治疗策略和更复杂的组合，这些组合只能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。我们将利用我们的系统帮助简化工业产品开发。一个额外的结果将是一个中央计算资源，我们的数据和模型将保存在一起，以及一个允许其他人与模型交互的软件接口。

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.