Host tissue recognition by complement factor H in the human eye: mapping changes with age and in AMD

英国超过一半的失明是由年龄相关性黄斑变性（AMD）引起的，全球约有5000万人受到影响。AMD是一种损害视网膜中心部分（称为黄斑）并导致中心视力丧失的疾病。越来越多的证据表明，患这种疾病的风险受到我们基因的强烈影响。最近的研究表明，一种特定基因（简称为补体因子H或CFH）的常见变异会大大增加患AMD的风险。这种变异（称为Y402H多态性）存在于大约35%的欧洲人中，它导致CFH蛋白发生微小但显著的变化，从而改变其功能特性。我们最近有了一个重要的发现？Y？然后呢？H？H？不同形式的CFH（分别为正常和致病）具有不同的识别眼睛中碳水化合物分子的能力。这可能会影响CFH蛋白的定位，这可能对AMD的病因和发展很重要，因为CFH是我们免疫系统的一部分，可以区分健康组织和患病组织。如果CFH蛋白不存在于正确的位置，那么免疫系统功能的破坏将导致组织损伤。我们提出AMD可能是由于眼睛内碳水化合物分子的年龄相关变化导致的，我们认为这会影响CFH的位置和功能。该研究项目的一个目的是通过在广泛的实验中分析来自不同年龄捐赠者的眼组织（由曼彻斯特眼库提供）来测试这一想法。除了正常的眼组织，我们还将检查AMD受影响的眼睛。这些研究是可能的，由于我们已经开发的分子工具，使我们能够看到（使用显微镜）在CFH结合位点在人体组织。我们在曼彻斯特的专业知识（例如AMD、CFH蛋白质和碳水化合物化学）将得到英国和美国科学合作者网络的补充，提供专业生物化学品和尖端技术。总的来说，这些研究可能会更好地了解AMD的病因，并可能有助于开发治疗这种疾病的新治疗策略。

Over half of blindness in the UK is caused by age-related macular degeneration (AMD), with about 50 million people affected worldwide. AMD is a disease that damages the central part of the retina (called the macula) and leads to central vision loss. There is mounting evidence that the risk of developing this disease is strongly influenced by our genes. Recent studies revealed that a common variant in one particular gene (known as Complement Factor H or CFH for short) strongly increases the risk of developing AMD. This variant (called the Y402H polymorphism) is present in about 35% of people of European decent and it results in a small, but significant, change in the CFH protein that alters its functional properties. We have recently made an important discovery that the ?Y? and ?H? forms of CFH (normal and disease-causing, respectively) have different abilities to recognise carbohydrate molecules in the eye. This may influence the localisation of the CFH protein, which is likely to be important to the cause and development of AMD since CFH is part of our immune system that distinguishes healthy from diseased tissues. If the CFH protein is not present in the correct location then a disruption to the function of the immune system would lead to tissue damage. We have proposed that AMD may result from age-related changes in the carbohydrate molecules within the eye, which we believe would influence CFH location and function. One aim of this research project is to test this idea by analysing eye tissues from donors of different ages (supplied by the Manchester Eye Bank) in a wide range of experiments. In addition to normal eye tissues we will also examine AMD-affected eyes. These studies are possible due to the molecular tools we have developed that allow us to look (using microscopy) at CFH-binding sites in human tissues. Our own expertise in Manchester (for example in AMD, the CFH protein and carbohydrate chemistry) will be complemented by a network of scientific collaborators (in the UK and USA) providing access to specialised biochemicals and cutting-edge technologies.Overall these studies are likely to lead to a greater understanding of the causes of AMD and may allow the development of new therapeutic strategies for treating this disease.