A mass spectrometry centre for the analysis of glycerolipids, glycerophospholipids and sphingolipids, and their lipid oxidation products

脂质是构成细胞周围膜的脂肪分子；没有它们，生命将不复存在。然而，这只是脂质在生物学中发挥的重要作用之一。例如，脂质也参与细胞内和细胞间多种形式的通讯，细胞膜的脂质成分影响嵌入其中的蛋白质的活性，比如那些将分子运送进和运出细胞的蛋白质。与氧反应对脂质造成的损害，就像食用油腐臭一样，与它们在疾病中的许多作用有关。因此，脂质分析和了解它们在生物学中的作用是非常重要的研究领域。然而，脂质的综合分析是具有挑战性的，因为它们是一组非常复杂的分子，在人类细胞中有超过10万种不同的类型，当包括细菌和其他微生物时，更多。它们中的许多具有非常相似的化学结构，因此很难区分它们，但它们的作用非常不同，因此正确识别它们非常重要。我们将用这笔资金购买的设备有一个额外的尺寸用于分子分离，基于它们的形状，这将大大增加我们能够区分的不同脂质的数量，并将使广泛的研究有助于理解它们在生物学中的复杂作用。有很多例子说明脂质在生活中是多么重要。例如，它们在控制细胞生长到细胞死亡中发挥作用，包括在炎症等情况下特别重要的过程。脂质还会影响细胞内蛋白质的活性，尤其是细胞膜上的蛋白质，而这些蛋白质是吗啡和胰岛素等药物的靶点。分析与膜蛋白相关的脂质，以及这些脂质变化对蛋白质活性的影响，对于理解这些影响以及它们如何随着年龄或饮食而变化，或在其他不同领域，如生物燃料的生产或细菌复制过程，可能成为抗菌剂的新靶点，是很重要的。脂质含有许多可被活性化学物质攻击的位点，这些受损的脂质本身可能具有生物活性或与其他分子发生反应，损害其功能。低密度脂蛋白，即有害胆固醇就是一个例子。低密度脂蛋白中脂质的氧化损伤被认为是导致心脏病发作和中风的原因。我们需要能够分析在这些反应中产生的不同脂质，它们是如何与生物系统相互作用或反应的，以及这对生物系统有什么影响。这项拨款提案将提供仪器，使我们能够进行复杂的分析，以自信地识别和测量复杂生物样品中存在的脂质量。使用的主要技术是质谱法，它可以非常精确地测量分子的重量，并能够分解分子以获得有关其结构的信息。然而，目前的方法并不总是能够分离复杂混合物中的所有单个成分以进行全面分析，特别是对影响细胞行为的低丰度分子。新仪器将提供额外的功能，通过额外的维度来分离分子，称为离子迁移率，它能够根据分子的形状分离分子。该设备将是第一个新设计的仪器，允许更精细的分子分离（它有一个循环离子迁移细胞，提供更长的有效分离路径长度）。这将使我们能够更准确地测量存在的脂质及其变化的方式，从而更好地理解许多重要领域的生物学。

Lipids are the fatty molecules that make up the membranes that surround cells; without them life would not exist. However, this is only one of the important roles that lipids play in biology. For example, lipids are also involved in many forms of communication within and between cells, and the lipid composition of the cell membrane affects the activity of proteins embedded in it, such as those that transport molecules in and out of the cell. Damage to lipids by reaction with oxygen, in the same way that cooking oils go rancid, is related to many of their roles in disease. Hence, the analysis of lipids and understanding their roles in biology are very important areas of research. However, the comprehensive analysis of lipids is challenging as they are a very complex set of molecules, with over 100,000 different types in human cells, and many more when bacteria and other microorganisms are included. Many of them have very similar chemical structures, making it hard to tell them apart, but very diverse effects, so it is important to identify them correctly. The equipment we will buy with this grant has an extra dimension for the separation of molecules, based on their shape, which will greatly enhance the number of different lipids that we are able to distinguish and will enable a wide range of research to help understand their complex roles in biology. There are many examples of how lipids are important in life. For example, they play a role in controlling cell growth to cell death, including processes particularly important in conditions such as inflammation. Lipids can also affect the activity of proteins in the cell, and particularly those in the cell membranes, many of which are targets for drugs such as morphine and insulin. Analysis of the lipids associated with membrane proteins, and the effects that changing of these lipids has on the activity of the proteins, is important in understanding these effects and how they may change with age or diet, or in other diverse areas, such as the production of biofuels or processes in bacterial replication that could be new targets for antimicrobials. Lipids contain many sites that can be attacked by reactive chemical species, and these damaged lipids can themselves have biological activity or react with other molecules impairing their function. An example is LDL, or bad cholesterol. Oxidative damage to the lipids in LDL is thought to be responsible for changes that lead to heart attacks and strokes. We need to be able to analyse the different lipids that are generated in these reactions, how they interact with or react with biological systems, and what effects this has on the biological system. This grant proposal is provide instrumentation that will allow us to perform the complex analysis required to confidently identify and measure the amount of lipids that are present in complex biological samples. The main technique to be used is mass spectrometry, which measures the weight of molecules very accurately, as well as being able to break up the molecules to get information on their structure. However, the current methods are not always able to separate all the individual components in complex mixtures to allow their full analysis, especially of low abundance molecules that affect cell behaviour. The new instrument will provide extra capabilities through an additional dimension for separation of the molecules, called ion mobility, which is able to separate molecule based on their shape. The equipment will be the first available of a new design of instrument that allows much finer separation of molecules (it has a cyclic ion mobility cell providing much longer effective separation path lengths). This will allow us to do more accurate measurement of the lipids present and the way in which they are changed, leading to a much better understanding of biology in many important areas.