Unravelling coupling between multiscale tissue mechanics and heart valve calcification

揭示多尺度组织力学与心脏瓣膜钙化之间的耦合

• 批准号: EP/X027163/2
• 负责人: Molly Stevens
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX027163%2F2
• 关键词: Unravelling; coupling; between; multiscale; tissue

Despite a high global prevalence and an immense clinical burden, the fundamental mechanisms of pathological aortic valve calcification remain largely elusive, hindering the development of potent therapeutic agents. In recent years, there has been an increasing interest in the regulatory role of mechanical forces, yet the bidirectional and spatiotemporal coupling between heterogeneous tissue mechanics and calcification remain poorly understood. In MechanoCal, I will develop a novel experimental-computational platform to unravel this complex interplay, by integrating in vitro microtissue technology, multiscale finite element modelling, and state-of-the-art multimodal characterisation techniques. I will engineer valve-mimicking, calcifying microtissues, that will be subjected to dynamic, multi-axial loading, resulting in heterogenous stresses. To quantify the tissue mechanical state, I will create a calibrated, multiscale finite element model, capturing the whole-tissue behaviour and the complex stress state around microcalcifications. I will leverage the expertise and in-house facilities for multimodal characterisation of the host group, to spatiotemporally monitor calcification and pathological cell differentiation in the microtissues. Finally, I will establish correlative maps between all the multidimensional biological, biochemical and biomechanical datasets to uncover mechanistic understanding of the complex mechanics-calcification coupling. These novel insights could impact drug discovery, cardiac biophysics modelling, and the design of tissue engineered heart valves.

尽管全球患病率很高且临床负担巨大，但病理性主动脉瓣钙化的基本机制在很大程度上仍然难以捉摸，阻碍了有效治疗药物的开发。近年来，人们对机械力的调节作用越来越感兴趣，但异质组织力学与钙化之间的双向和时空耦合仍然知之甚少。在 MechanoCal，我将开发一个新颖的实验计算平台，通过集成体外微组织技术、多尺度有限元建模和最先进的多模态表征技术来阐明这种复杂的相互作用。我将设计模拟瓣膜的钙化微组织，该组织将承受动态多轴载荷，从而产生不均匀的应力。为了量化组织机械状态，我将创建一个校准的多尺度有限元模型，捕获整个组织行为和微钙化周围的复杂应力状态。我将利用专业知识和内部设施对宿主组进行多模式表征，以时空监测微组织中的钙化和病理细胞分化。最后，我将在所有多维生物、生化和生物力学数据集之间建立相关图，以揭示对复杂力学-钙化耦合的机制理解。这些新颖的见解可能会影响药物发现、心脏生物物理学建模和组织工程心脏瓣膜的设计。