Investigating age-dependent regulation of complement in human eye tissues: implications for Age-related Macular Degeneration

在英国，超过一半的失明病例是由老年性黄斑变性(AMD)引起的，全球约有5000万人受到影响。AMD是一种损害视网膜一部分(称为黄斑)并导致中央视力丧失的疾病。虽然这与饮食和环境因素有关，但有明确的证据表明，患这种疾病的风险强烈地受到我们的基因的影响。最近的研究表明，一种特定基因的常见变异(简称补体因子H或CFH)会极大地增加患AMD的风险。这种变异(称为Y402H多态)存在于大约35%的欧洲人后裔中，它导致CFH蛋白发生微小但显著的变化，改变其功能特性。我们最近有了一个重要发现，即正常形式和疾病相关形式的CFH(分别称为“402H”和“402Y”)在识别眼睛中特定的一组碳水化合物分子(称为GAG)的能力上有所不同。这可能会影响CFH蛋白的定位，这可能对AMD的发展很重要，因为CFH控制着我们区分健康和疾病组织的免疫系统的一部分。如果CFH蛋白没有出现在正确的位置(或者只是存在较少的CFH蛋白)，就像我们认为的402H型CFH的情况一样，那么由此导致的免疫系统破坏将导致炎症和组织损伤；即AMD的主要特征。根据我们最近(由MRC资助)的实验，我们有初步证据表明，与年龄相关的人眼变化似乎会影响CFH功能。我们认为，眼睛的正常变化，发生在衰老过程中，可能对AMD的发展很重要，特别是对于那些具有风险遗传特征的人(例如，那些具有402H形式的CFH的人)。因此，这项研究项目的一个目的是通过分析不同年龄(即从30岁到80岁以上的人)捐赠者的眼睛组织来测试这一想法，这些组织将由曼彻斯特眼科银行提供。例如，我们将描述GAG的结构如何随年龄变化，以及这如何影响402H和402Y形式的CFH的功能。据我们所知，这是一种独特的方法，其他小组没有采取这种方法，他们主要关注AMD的后期阶段，即当组织损伤已经发生时。我们还发现了发生在健康人眼中的其他变化，这些变化可能另外有助于AMD的发生和发展。我们的目标是更详细地研究这些重要的新发现，以确定它们是否有助于设计AMD的改进治疗方法，这可能是疾病过程的早期靶点。如果他们这样做了，我们将处于有利地位(即拥有必要的经验/设施)，将我们的发现从实验室转化为临床。我们自己在曼彻斯特的专业知识，例如在AMD方面，CFH蛋白质和碳水化合物化学(以及我们在过去8年开发的分子工具)将得到(英国和国外的)科学合作者网络的支持，提供专业的生物化学和尖端技术。所有这些独特和新颖的研究可能会导致对AMD病因的更多了解，并可能允许开发治疗这种毁灭性疾病的新治疗策略。

Over half of all cases of blindness in the UK are caused by Age-related Macular Degeneration (AMD), with about 50 million people affected worldwide. AMD is a disease that damages a part of the retina (called the macula) and leads to central vision loss. While there are associations with diet and environmental factors, there is clear evidence that the risk of developing this disease is strongly influenced by our genes. Recent studies revealed that a common variant of 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 descent 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 normal and disease-associated forms of CFH (referred to as '402H' and '402Y', respectively) differ in their ability to recognise a particular group of carbohydrate molecules (called GAGs) in the eye. This may influence the localisation of the CFH protein, which is likely to be important to the development of AMD since CFH controls part of our immune system that distinguishes healthy from diseased tissues. If the CFH protein is not present in the correct location (or if there is simply less of it), as we believe is the case for the 402H form of CFH, then the resulting disruption of the immune system would lead to inflammation and tissue damage; i.e. major features of AMD. Based on our recent (MRC-funded) experiments we have preliminary evidence for age-related changes in the human eye that appear to influence CFH function. We think it likely that normal changes in the eye, which occur during ageing, may be important in the development of AMD, in particular for individuals with an 'at-risk' genetic profile (e.g. those having the 402H form of CFH). Therefore, one aim of this research project is to test this idea by analysing eye tissues from donors of different ages (i.e. ranging from 30 year olds to those over 80), which will be supplied by the Manchester Eye Bank. For example, we will characterise how the structure of GAGs change with age and how this influences the functions of the 402H and 402Y forms of CFH. To our knowledge, this is a unique approach that is not being pursued by other groups, who are mainly focusing on the later stages of AMD, i.e. when tissue damage has already occurred. We have also identified other changes that occur in healthy human eyes that might additionally contribute to the initiation and progression of AMD. We aim to investigate these important new discoveries in further detail to determine whether they might be useful in the design of improved treatments for AMD, which could potentially be targeted early in the disease process. If they do, we are well placed (i.e. with the necessary experience/facilities) to translate our findings from the laboratory to the clinic.Our own expertise in Manchester, for example in AMD, the CFH protein and carbohydrate chemistry (along with the molecular tools we have developed over the last 8 years), will be supported by a network of scientific collaborators (both in the UK and abroad) providing access to specialised biochemicals and cutting-edge technologies.Overall these unique and novel 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 devastating disease.