Imaging dynamics in biophysical/biochemical processes across the hierarchical scales (BioPro Network)

生物组织和器官随着时间经历动态的结构和化学变化的持续状态，范围从我们的关节组织在行走时的弹性回缩到随着我们年龄的增长缓慢的组织分解，到细胞对感知到的机械力的非常快速的分泌和反应。生物组织在结构和功能上都具有层次性，蛋白质和DNA结构在纳米尺度上通向细胞，纤维状细胞外基质在微米尺度上通向最大尺度的器官。这些器官在动态环境中的运作方式不能仅仅从基因上推断出来，而必须考虑到在多个层面上发生的过程。一个经典的例子是我们的关节是如何随着年龄的增长而恶化的，在分子水平上，这是由蛋白质水平和组成决定的，在更高的水平上，它们如何以不同的方式聚集成弹性更差的纤维，在更高的(微观)水平上，细胞如何通过改变它们分泌的蛋白质来对外部负荷做出反应，最后在整个器官的水平上，细胞/组织阵列如何变得更具弹性并随着时间的推移而分解。一个巨大的挑战是理解这一动态过程的层次是什么，以及它们如何影响组织功能、生长和疾病。然而，目前生物医学领域使用的物理科学和工程方法缺乏在接近活组织的条件下同时在多个水平上动态成像这些过程的能力。然而，这是可能的，因为最近在中央研究设施(如同步加速器)基于物理科学的高能成像方法方面取得了进展，这些方法是专门的方法，如3D X射线成像、微焦点衍射、激光扫描方法，以及使用自由电子激光来观察分子以比以前可能的速度快许多数量级的速度振动。挑战是将这些与生理上真实的环境结合起来，使生物物理/化学过程的动力学成像成为可能，连接这些过程的巨大时间和空间尺度，并最终将这些技术首先转化为实验室，然后进入临床。在这个网络中，我们将努力使这一潜力成为现实，将英国领先的物理科学和工程研究人员与生物医学研究人员聚集在一起，共同努力应对工程和生物挑战。我们将集中在三个领域：i)使用这些高能方法开发实验装置，使组织/细胞/器官保持在自然状态；ii)设计方法以跨技术相互关联信息；iii)将在不同长度尺度上获得的信息链接到统一的图像中。我们的项目将专注于多种规模的肌肉骨骼退化，但我们将寻求开发尽可能广泛适用于其他条件的方法。我们将运行几个短期概念验证项目，使这些团队能够测试新想法及其是否有效，并资助研究人员在彼此的实验室进行短期访问，这将有助于从物理科学转移到生物科学。如果这些结果显示出希望，它们将导致全面的项目，在这些项目中，生物医学或临床相关的应用程序可以得到全面开发。我们将举办一系列活动，以探索和确定挑战(沙坑和讲习班)，并介绍和分析结果(年度会议)。我们开发的方法和工具将广泛提供给广大学术界，以使其更快地惠及广大公众。简而言之，我们的网络将提供关键的试验场，在这里，只有中央设施才能获得的用于分析复杂物质的最先进的高能技术被改造并应用于解决生命科学和医学中的关键问题。

Biological tissues and organs undergo a constant state of dynamical structural and chemical changes with time, which can range from our joint tissues elastic recoil during walking to the slow tissue breakdown as we age, to the very rapid secretion and reaction of proteins by cells in response to sensed mechanical forces. Biological tissues are hierarchical in both structure and function, with protein and DNA architecture at the nano scale leading up to cells and fibrous extracellular matrices at the micron scale to organs at the largest scale. The way such organs operate in a dynamic environment cannot be inferred solely from the gene, but must take into account the processes happening at multiple levels. A classic example is how our joints deteriorate with age, which is - at the molecular level - governed by how proteins levels and composition, at one level higher how they aggregate differently into fibres with poorer elasticity, at a level higher still (microscopic) in how cells react to external loads by changing what proteins they secrete, and finally at the level of the whole organ in how the cell/tissue array becomes less resilient and breaks down with time. A grand challenge is to understand both what this hierarchy of dynamical processes are as well as how they affect tissue functioning, growth and disease. Currently, however, physical-science and engineering methods used in the biomedical field lack the capacity to image these processes dynamically, in a condition close to the living tissue and at multiple levels simultaneously. However, this is potentially possible, due to recent advances in physical-science based high energy imaging methods at central research facilities (like synchrotrons) in specialist methods like 3D X-ray imaging, microfocus diffraction, laser-scanning methods and the use of free-electron lasers to watch molecules vibrate at speeds many orders of magnitude faster than was previously possible. The challenge is coupling these with physiologically realistic environments to enable the imaging of dynamics of biophysical/chemical processes, bridging the huge temporal and spatial scales of these processes, and finally translating these technologies first to the laboratory and then into the clinic. In this network, we will work to make this potential a reality by bringing together leading physical-science and engineering researchers in the UK with biomedical researchers to attack the engineering and biological challenges in a team-effort. We will focus on three areas: i) developing experimental setups using these high energy methods which keep the tissue/cell/organ in a native state ii) devising methods to cross-correlate the information across techniques and iii) linking information obtained at different length scales into a unified picture. Our projects will focus on musculoskeletal degeneration at multiple scales, but we will seek to develop methods that are as widely applicable to other conditions as possible.We will run several short-term proof of concept projects which will allow these teams to test new ideas and whether they work, and fund researchers to spend short-term visits in each other's labs which will help transfer from the physical to the biological sciences. If these results show promise, they will lead to full-scale projects where a biomedically or clinically relevant application can be developed in full. We will hold a range of activities to explore and identify challenges (sandpits and workshops) and to present and analyse the results (annual conferences). The methods and tools we develop will be made widely available to the general academic community to bring them sooner to benefit the general public. Our network, in short, will provide the key proving-ground where the most advanced high energy techniques to analyse complex matter, available only at central facilities, are adapted and made applicable to solve critical questions in the life- and medical-sciences.