Core support for collaborative glycomic and proteomic research

我们大多数人都听说过DNA，知道它是生命的基本模板，知道它如何编码一种叫做蛋白质的分子，这种分子在构成像人类一样复杂的生物体的数十亿个细胞内和细胞之间执行许多基本任务。当两组关键分子出现问题时，要么是DNA，要么是由DNA产生的蛋白质，那么生物就会迅速经历功能的退化，我们将其归类为疾病状态。许多现代生物学研究的目标是了解分子水平上的问题是如何出现的，以及我们如何纠正这些问题，从而为人类健康做出重大贡献。但是说生命系统中只有两种关键类型的分子是过于简单化了：还有其他的，我们帝国理工学院的研究小组认为，通常被称为糖或碳水化合物的分子值得特别关注，因为它们可以而且确实在分子和细胞相互识别的方式中发挥着重要的潜在作用，因此它们在促进整个身体的健康或疾病方面具有相互作用。我们身体里的每个细胞都包裹着一层富含糖的层，叫做糖萼。作为“身份标签”，糖萼外围被称为聚糖的糖链与各种受体（识别分子）相互作用，从而帮助控制细胞的社会（正确）和反社会（错误）行为。帝国实验室专门从事高灵敏度筛选和结构技术的开发和利用，涉及先进的质谱仪器，用于表征重要聚糖的详细结构，从而更好地了解这些相互作用是如何发生的，以及当事情出错时我们如何在分子水平上进行干预。现在有许多引人入胜的聚糖介导的生物现象的例子需要我们进一步了解：寄生虫是如何伪装自己对抗宿主免疫系统的？为什么发育中的胎儿没有被他们的母亲发现并作为“外国人”拒绝？血液中循环的防御性白细胞如何知道何时进入病变组织对抗感染？我们和其他人相信，当我们充分了解细胞表面的聚糖如何与聚糖结合蛋白结合以介导粘附和信号事件时，这些以及与生物识别相关的问题将得到解决。让我们从哲学的角度来看上面的一个例子，它与我们对免疫学的理解有关，免疫学作为一门学科是这项资助的一个关键研究领域。上面一个孕妇的例子代表了一个非常重要的免疫学难题。我们知道我们的器官携带特定类型的免疫标记，除非这些标记匹配，否则移植的器官将被排斥。在正常怀孕的情况下，与胎儿相关的免疫标记有一半来自父亲，通常对母亲来说是外来的。然而，我们也知道女性可以通过使用体外受精技术成为代孕母亲。在代孕的情况下，这些免疫标记可能都不匹配。因此，核心问题是为什么母亲不排斥胎儿？现在很明显，母亲建立了一个“免疫抑制盾牌”，阻止她自己的免疫反应，这样胎儿就不会被排斥。然而，介导这种“屏蔽”的分子相互作用尚不清楚。我们的假设是，体液中细胞和蛋白质的糖衣在免疫抑制中起着至关重要的识别作用，我们目前的拨款提案的一部分是寻求获得实验证据来解决这一假设，从而为处理感染开辟潜在的新途径。

Most of us have heard about DNA, how it is the basic template of life, and how it codes for molecules called Proteins which carry out many of the fundamental tasks both in and between the billions of cells which make up a living organism as complex as a human being. When things go wrong with the two key sets of molecules, either the DNA or the Proteins produced from it, then the living being can rapidly experience a deterioration of function which we classify as a disease state. Much of modern biological research is targeted at understanding how things can go wrong at the molecular level, and how we might correct them and thus make significant contributions to human health. But to say that there are just two key types of molecules in living systems is an over-simplification: there are others, and our Group at Imperial believes that the molecules commonly called Sugars or Carbohydrates deserve special attention because of the major potential role they can and do have in the way that molecules and cells recognise each other and therefore the interactions they have in the promotion of health or disease in the body as a whole. Every cell in our body is coated with a sugar-rich layer called the glycocalyx. Acting as 'identity tags', chains of sugars called glycans on the periphery of the glycocalyx interact with a whole variety of receptors (recognition molecules) and thereby help to control the social (correct) and anti-social (errant) behaviour of cells. The Imperial laboratory specialises in the development and exploitation of high sensitivity screening and structural techniques involving advanced mass spectrometric instrumentation for characterising the detailed structure of important glycans and thus providing a better understanding of how these interactions take place and how we might intervene at the molecular level when things go wrong. There are now numerous examples of fascinating glycan-mediated biological phenomena which demand our further understanding: How does a parasite camouflage itself against its host immune system? Why are developing foetuses not detected and rejected as 'foreign' by their mothers? How do defensive white blood cells circulating in the bloodstream know when to enter diseased tissues to fight infection? We, and others, believe that these and related questions about biological recognition, will be solved when we fully understand how glycans on cell surfaces engage with glycan-binding proteins to mediate adhesive and signalling events. Let us take a philosophical look at just one of the above examples which relates to our understanding of immunology, which as a discipline is a key area of research on this grant. The example of a pregnant woman above represents a very significant immunological puzzle. We know that our organs carry specific types of immune markers and, unless these markers match, transplanted organs will be rejected. In the case of normal pregnancy, half of the immune markers associated with the foetus will come from the father and are usually foreign to the mother. However, we also know that women can become surrogate mothers by using in vitro fertilisation techniques. In the case of surrogate pregnancy, none of these immune markers may match. Therefore the central question is why does the mother not reject her foetus? It is now evident that the mother sets up an 'immunosuppressive shield' that blocks her own immune response so that the foetus is not rejected. However the molecular interactions mediating this 'shielding' are not understood. Our hypothesis is that the sugar coats of cells and of proteins in body fluids play a vital recognition role in immune suppression, and part of our current grant proposal seeks to acquire the experimental evidence to address this hypothesis, thereby opening up potential new avenues for dealing with infection.