Multi-user, multi-centre MRI to reduce and refine the use of mice in cancer and trauma research

非侵入性成像技术允许研究人员通过跟踪同一动物一段时间内的疾病并从每种动物那里获得更多信息来减少科学研究中使用的动物数量。这些信息可以是解剖学的(例如肿瘤的大小和位置、脑损伤)，也可以是功能性的(例如测量组织或器官内的细胞正在做什么，例如它们是否在生长)。我们的研究经常需要使用转基因(转基因)模型，在这种模型中，小鼠自然地患上癌症，其方式与人类相似。这类研究的主要挑战是准确测量癌症的发展和肿瘤对新疗法的反应，并将其与当前的标准进行比较。这类研究在人类疾病中是共有的。在我们的一个胰腺癌基因工程小鼠模型中，动物在出生后80-150天的时间内自发产生肿瘤。这些肿瘤的发展速度是不同的，因为肿瘤通常发展到身体组织的深处，它们在外部是不可见的，只有当它们变得可触到或动物生病时才明显。如果我们能检测到较小的肿瘤，每种动物都可以用于肿瘤发展的早期阶段，这将减少动物的痛苦和浪费。随着磁共振成像(MRI)的使用，我们将能够更早地发现肿瘤，并与其他动物的大小匹配，以便有相关的对比组。这些肿瘤可以使用成像方案检测出来，这些成像方案根据组织的脂肪和水分含量显示组织之间的良好对比度，是查看腹部软组织的理想选择。这将使我们能够确定治疗计划和治疗反应-类似于患者的治疗方式。此外，使用定制的鼠标支架，动物可以在麻醉下从核磁共振仪器转移到我们的其他成像相机。通过这种方式，MRI可以与放射性示踪剂成像(正电子发射断层扫描(PET)和单光子发射断层扫描(SPECT))相结合。高分辨率的解剖核磁共振扫描将使我们能够识别放射性信号是否起源于肿瘤组织或周围组织，如肠和肾。然后我们将能够量化肿瘤放射性示踪剂的积累。通过使用测量生物功能(如增殖)的放射性探针，我们将能够测量肿瘤在不同时间点对不同治疗方法的反应。我们目前的解剖成像方法不能让我们区分肠道和肿瘤等组织，但MRI将使我们能够做到这一点。MRI也将在我们对小鼠神经创伤和创伤后多器官衰竭模型的研究中发挥无价的作用。神经创伤组对调节急性神经炎、将长期组织损伤降至最低以及测试新的治疗方法特别感兴趣。利用核磁共振获得的信息(例如脑肿胀、出血、血脑渗透性、白质和灰质损伤)，结合神经行为测试，将有助于我们减少研究的动物数量，并更准确地判断我们的终点。这将确保实验尽快结束。MRI是观察器官功能障碍模型中的解剖结构变化和炎症性损害(如水肿)的理想方法，而且还将减少参与这些研究的动物数量。我们还将修改目前使用MRI进行生物发光成像(BLI)的方法。BLI是一种2D技术，不提供动物体内肿瘤深度的信息。将这些图像与3D-MRI相结合，将使我们能够更准确地校正肿瘤深度并量化BLI信号。这将使我们能够匹配具有相似肿瘤负担的动物，减少生物变异并减少群体数量。

Non-invasive imaging techniques allow researchers to reduce the numbers of animals used in scientific research through following disease in the same animal over time and obtaining more information from each animal. This information can be anatomical (e.g. tumour size and location, brain damage) or functional (e.g. measuring what the cells within the tissue or organ are doing, such as whether or not they are growing). Our studies often require the use of genetically modified (transgenic) models where mice naturally develop cancers in a fashion similar to that of humans. The main challenge in such studies, which is shared in human disease, is to measure, accurately, the development of the cancer and the response of the tumour to new treatments and compare it with the current standard. In one of our genetically engineered mouse models of pancreatic cancer, the animals develop tumours spontaneously after birth over a time period of 80-150 days. The rate at which these tumours develop is variable and because the tumours normally develop deep within the tissues of the body they are not externally visible and are only apparent when they become palpable or the animal becomes ill. If we could detect smaller tumours, every animal could be used at an earlier stage of tumour development, which would reduce suffering and waste of animals. With the use of Magnetic Resonance Imaging (MRI) we will be able to detect tumours earlier and size match with other animals in order to have a relevant comparative groups. These tumours are detectable using imaging protocols that show excellent contrast between tissues according to their fat and water content, ideal for looking at the soft tissues in the abdomen. This will enable us to determine treatment schedules and therapeutic responses - similar to the way patients are treated. In addition, using a custom-made mouse holder, the animal can be transferred under anaesthetic from the MRI instrument to our other imaging cameras. In this way MRI can be combined with radiotracer imaging (positron emission tomography (PET) and single photon emission tomography (SPECT)). The high resolution anatomical MRI scans will allow us to identify whether the radioactive signal originates in tumour tissue in or surrounding tissues such as intestine and kidney. We will then be able to quantify the tumour radiotracer accumulation. By using radioactive probes that measure biological functions such as proliferation, we will be able to measure tumour function in response to different therapeutics at different time-points. Our current methods of anatomical imaging don't allow us to distinguish between tissues such as intestine and tumour but MRI will enable us to do this work.MRI will also be invaluable in our research in mouse models of neuro-trauma and multiple organ failure following trauma. The Neuro-Trauma group has a particular interest in modulating acute neuroinflammation, minimising long term tissue damage and testing new therapeutic approaches. Having access to information gained from MRI (e.g. brain swelling, haemorrhage, blood brain permeability, white and grey matter damage), combined with neuro-behavioural testing would help us to reduce the numbers of animals studied and be more accurate with our endpoints. This would ensure that the experiments would end as soon as possible. MRI is ideal for looking at anatomical structural changes and inflammatory lesions, such as oedema, in organ dysfunction models and again would reduce the numbers of animals being entered into these studies. We will also modify our current method of bioluminescence imaging (BLI) using MRI. BLI is a 2D technique and gives no information about tumour depth within the animal. Combining these images with 3D-MRI will allow us to correct for tumour depth and quantify the BLI signal more accurately. This will enable us to match animals with similar tumour burdens, reduce biological variation and decrease group numbers.