A globally unique 19F, 13C, 15N NMR system to enable frontier bioscience

我们使用一种称为核磁共振波谱 (NMR) 的技术来研究构成细胞和生物体复杂机制的生物分子的结构。它们的结构决定了它们如何工作和相互作用，并构成了人类理解尖端生物科学的巨大努力的基础。我们提议购买世界上第一个 TXO-HF NMR 低温探针技术，并利用它在帕金森病等神经退行性疾病、设计新生物分子的结构或生产抗病毒、抗生素和抗真菌化合物等领域做出突破性的发现。我们还可以利用这些新的 NMR 数据来设计或重新利用药物，使它们更有效，甚至可以观察当您的身体尝试代谢下一代药物时会发生什么。我们已经确定了超过 3000 万英镑的资助研究项目、国家合作和博士培训项目，该仪器从第一天起就将支持这些项目，并且我们正在与一系列国家网络合作，这些网络将使我们能够在 NMR 仪器的使用寿命内大幅增加这一项目。新探头将使这项研究成为可能，因为核磁共振与医院中使用的全身核磁共振扫描仪具有相同的基本原理。然而，在生物科学中研究分子时，很难获得足够的样本来用我们的核磁共振波谱仪进行检测，而核磁共振研究的“标准”原子核（质子）往往非常丰富，以至于它会给出非常“嘈杂”的光谱，其中包含太多信号，我们无法解释。这些问题的解决方案是使用核磁共振“冷冻探针”，该探针具有非常灵敏的检测能力，并且经过优化，可以观察往往会产生更多扩散信号的其他类型的原子核。一些 NMR 系统已经开始使用碳核和氮核，但我们要安装的这个 TXO-HF 系统特别强大的原因是它还可以使用另一个核，即氟，氟作为探针具有独特的强大功能，因为它在大多数自然系统中很少见。这意味着我们可以使用尖端的生物合成技术将氟引入我们研究的分子中，然后在没有基于质子的 NMR 发现的所有背景噪音的情况下跟踪它的行为，从而研究生物学中的一些非常困难的问题。这种新设备有许多更重要、更复杂的科学问题需要回答，为此，我们与许多合作大学、国家核磁共振网络项目和生物制药公司合作。通过将所有这些不同的群体聚集在一起，我们确保最大限度地增加人员数量，并拥有广泛的专业知识，可以应用于我们面临的科学挑战。随着全国大学合作方式的发展，共享（昂贵！）这样独特而复杂的设备变得越来越重要。因此，我们寻求使用该设备的部分目的是将其作为范例，鼓励运行这些仪器的熟练研究技术专业人员进行合作和培训，并激励学生自己将继续成为未来的生物科学研究人员和核磁共振波谱学家。为此，我们与一支专门的团队合作，他们拥护这一想法，我们希望通过他们使设备更具影响力和可持续性。

We use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) to study the structure of biomolecules that form the intricate machinery of cells and organisms. Their structure determines how they work and interact with each other and forms the basis of considerable human effort in understanding cutting edge bioscience. We are proposing to purchase the world's first TXO-HF NMR cryogenic probe technology and use it to make ground-breaking discoveries in areas such as neurodegenerative conditions like Parkinson's disease, design the structure of new biomolecules, or the production of antiviral, antibiotic and antifungal compounds. We can also use this new NMR data to design or repurpose drugs to make them more potent and even look at what happens to next generation drugs when your body tries to metabolise them. We have already identified >£30m of funded research programs, national collaborations and doctoral training programs that this instrument will underpin from day one, and we are working with a range of national networks who will allow us to increase this substantially over the lifetime of the NMR instrument. The new probe will enable this research because NMR shares the same basic ideas as the whole-body MRI scanners that are found in hospitals. However when studying molecules in bioscience, it is difficult to get enough sample to detect with our NMR spectrometer and the 'standard' atomic nucleus that MRI studies (the proton), tends to be so abundant that it gives very 'noisy' spectra with too many signals for us to be able to interpret. The solution to these problems is to use an NMR 'cryoprobe' that has very sensitive detection and is optimised to look at other types of atomic nuclei that tend to give more spread-out signals. Some NMR systems have started to use carbon and nitrogen nuclei, but what makes this TXO-HF system we are going to install especially powerful is that it can also use a further nucleus, fluorine, that is uniquely powerful as a probe because it is rare in most natural systems. This means we can use cutting-edge biosynthetic techniques to introduce fluorine into the molecules we study and then follow it's behaviour without all of the background noise that is found with proton-based NMR and thus study some very difficult problems in biology. There are many more important and complex scientific questions to answer with this new equipment and to do this we have teamed up with many partner universities, national NMR network programs and biopharmaceutical companies. By bringing all of these different groups together we are ensuring we maximise the number of people and have a broad expertise that can be applied to the scientific challenges we face. As the national picture of how universities work together evolves, sharing (expensive!) unique and sophisticated equipment like this becomes ever more important. Therefore part of what we are seeking to do with this equipment is use it as an exemplar to encourage collaboration and training for our skilled research technical professionals who run these instruments, as well as to inspire the students who themselves will go on to be the bioscience researchers and NMR spectroscopists of the future. To do this we have engaged with a dedicated team who champion this idea and through which we hope to make the equipment even more impactful and sustainable.