Systems-Mechanobiology of Health and Disease

系统生物学是我们成功整合基础研究和复杂疾病(包括英国的主要杀手：癌症、心血管疾病和神经退行性疾病)所产生的大量定量生物学数据的基础。数学方法论是实现这种集成的关键，并开发能够利用患者特定数据进行精确医学应用、改进诊断和优化个性化治疗的预测模型。当前的系统-生物模型专注于多组学数据(例如基因组和蛋白质组数据)的集成，但在很大程度上忽略了最近的研究发现在推动一大类疾病中至关重要的签名：机械签名。力学特征包括细胞外基质僵硬和重新排列，细胞内力的改变和血流障碍。这些疾病发生在各种各样的情况下，如实体瘤、动脉粥样硬化、心脏纤维化或肝硬变。至关重要的是，我们现在知道这些机械信号是由细胞感知的，并可以激活细胞内通路，从而进一步推动疾病的发展、进展和治疗反应。然而，到目前为止，机械信息在系统生物学中被忽视。这主要是因为缺乏数学方法论：系统生物学和力学都建立在数学形式主义的基础上，但它们在历史上是由不同的科学界孤立发展起来的。通过这一奖学金，我将发展迫切需要的数学方法论，然后将其应用于推进一类新的模型，这些模型提供对细胞和组织的机械和非机械特征的双向相互作用的基本见解。为了最大限度地提高模型的预测能力，我将成立一个跨学科的研究小组，由建模师和实验者共同努力，通过稳健的迭代过程开发数据驱动的模型和新颖的实验。这项工作计划将极大地推进系统和机械生物学之间的实验研究，该领域研究生物的机械特征。在头四年，我将专注于发展数学方法、模型和体外实验，以获得关于细胞和组织的机械和非机械特征相互作用的基本科学见解。这项工作的重点将是实体肿瘤；然而，我将与专家合作，例如心血管科学家，以测试我的方法对其他疾病模型的适用性。此外，我还将与生物医学研究和制药行业的专家团队密切合作，以最大限度地发挥这项工作的翻译潜力。我将从这个项目的第5年开始执行具体的翻译工作。这项工作，加上量身定做的全面培训计划，将使我能够在这个新形成的领域--系统-机械生物学--确立自己的领导地位。该领域将首次将模型师、生物学家、临床医生和行业聚集在一起，通过新的系统-机械生物学方法解决广泛的生物医学问题，包括癌症、心血管和神经退行性疾病以及再生医学。

Systems biology underpins our success in integrating the wealth of quantitative biological data generated from basic research as well as from studying complex diseases, including the UK's major killers: cancer, cardiovascular and neurodegenerative diseases. Mathematical methodology is critical to achieve this integration, and to develop predictive models that can utilise patient specific data for precision medicine applications, improving diagnostics and optimising personalised treatments.Current systems-biology models focus on the integration of multi-omics data (e.g. genomic and proteomic data), but largely neglect signatures that recent research identified to be of critical importance in driving a large class of diseases: mechanical signatures. Mechanical signatures include stiffened and realigned extracellular matrix, alterations in intracellular forces and obstructions of blood flow. These occur in a broad range of conditions such as solid tumours, atherosclerosis, cardiac fibrosis or liver cirrhosis. Crucially, we now know that these mechanical signatures are sensed by cells and can activate intracellular pathways that may further drive disease development, progression and treatment responses.However, to date, mechanical information is neglected in systems biology. This is mainly due to the lack of mathematical methodologies: systems biology and mechanics are both based on mathematical formalism, yet they were historically developed in isolation by distinct scientific communities. Through this fellowship, I will develop the urgently needed mathematical methodology and then apply it to advance a new class of models that provide fundamental insights into the bi-directional interplay of mechanical and non-mechanical signatures of cells and tissues. To maximise the predictive capabilities of the models, I will form a transdisciplinary research group with modellers and experimentalists working together to develop data-driven models and novel experiments through a robust iterative process. This programme of work will then greatly advance experimental research at the interface of systems - and mechanobiology, the field studying mechanical signatures of biology.In the first four years, I will focus on developing mathematical methodology, models and in-vitro experiments to gain fundamental scientific insights into the interplay of mechanical and non-mechanical signatures of cells and tissues. The focus of this work will be on solid tumours; however, I will engage with experts, e.g. cardiovascular scientists, to test the applicability of my methods to other disease models. Moreover, I will also work closely with a team of experts from biomedical research and the pharmaceutical industry to maximise the translational potential of this work. I will perform specific translational work from year 5 of this project. This work, together with the tailored and comprehensive training programme, will enable me to establish myself as a leader in this newly formed field, systems-mechanobiology. This field will, for the first time, bring together modellers, biologists, clinicians and industry to tackle a wide range of biomedical problems - including cancer, cardiovascular and neurodegenerative diseases and regenerative medicine - through the new systems-mechanobiology approach.