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

系统模拟真皮细胞外基质维持中与年龄相关的变化：机制和干预措施。

• 批准号: NC/S001050/1
• 负责人: Daryl Shanley
• 金额: $ 50.18万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FS001050%2F1
• 关键词: Systems; modelling; age; related; changes; Systems; modelling; age; related; changes

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.

与皮肤结构相关的年龄相关的变化，例如纤维，皱纹和柔韧性损失是皮肤外细胞外基质（ECM）调节和组成的变化的结果。随着年龄降低ECM降低的过程，ECM倾向于在再生过程中占主导地位。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的疾病发生率的增加。针对这些变化的因果机制的先进抗衰老皮肤护理产品是一个数十亿英镑的行业，预计在未来几十年中会增加。然而，对这些机制仍然未知，并且对维持ECM所涉及的过程的深入了解将提供更好的产品，并且 - 更重要的是，我们对皮肤老化过程本身的理解也进一步。在护肤产品开发中使用动物是广泛的，但由于人类生物学的根本差异，不一定非常有用。在英国出售的化妆品中的动物测试首先被禁止进行1998年在英国进行的测试，并于2009年在欧盟进行，并于2013年延伸到所有国家。但是，许多动物，尤其是实验室小鼠，尤其是在基础研究中使用的，从而确定了新型皮肤医疗保健产品。在这里，我们旨在使用一种集成硅内发现和体外验证的系统生物学方法，以提供动物实验的有力替代方案。我们将使用这种方法来生成人类真皮维护ECM的年龄相关变化的计算机模型，并使用它们来确定干预策略以抵制不良变化。我们的计算模型将通过人类真皮细胞产生的数据告知，从而避免专注于仅在动物模型中相关的过程。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，这些组合仅在实验室实验中进行。这些看起来很有希望的治疗方法将在我们开发的维特罗体系中进行测试，我们已经开发出非常像人类皮肤的行为。我们的体外真皮模型使我们可以密切控制组织内生长哪些细胞以及如何研究它们。我们将使用我们的系统来帮助简化行业的产品开发。额外的结果将是一种中央计算资源，我们的数据和模型将被放在一起，以及一个软件接口，以允许其他人与模型进行交互。