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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

基本信息

批准号：
EP/X027163/1
负责人：
Molly Stevens
金额：
$ 26万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FX027163%2F1
关键词：
Unravelling coupling between multiscale tissue

项目摘要

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.

尽管全球患病率高，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，但异质组织力学和钙化之间的双向和时空耦合仍然知之甚少。在MechanoCal，我将开发一种新的实验计算平台，通过整合体外微组织技术，多尺度有限元建模和最先进的多模态表征技术来解开这种复杂的相互作用。我将设计出模拟瓣膜的钙化微组织，它将承受动态的多轴载荷，从而产生异质应力。为了量化组织的机械状态，我将创建一个校准的多尺度有限元模型，捕获整个组织的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，我将建立所有多维生物，生物化学和生物力学数据集之间的相关映射，以揭示复杂的力学-钙化耦合的机理理解。这些新的见解可能会影响药物发现，心脏生物物理建模和组织工程心脏瓣膜的设计。