Molecular role of metal-induced complement protein aggregation in age-related macular degeneration

金属诱导的补体蛋白聚集在年龄相关性黄斑变性中的分子作用

• 批准号: G0801724/1
• 负责人: Stephen Perkins
• 金额: $ 40.77万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801724%2F1
• 关键词: Molecular; role; metal; induced; complement

Our immune system is vital to protect us from all types of bacterial, fungal and viral infections. There are different types of immune defence in the body, and that relevant to this proposal is called ?innate immunity? in which blood proteins called ?complement? acts to destroy invading foreign bacteria. While highly effective against bacteria, complement requires tight control so that it does not attack the body?s own cells. This control is achieved by a series of regulatory proteins, and Factor H is one such protein. In recent years, Factor H has been implicated in age-related macular degeneration, the most common cause of blindness in old age. The disease, which results in loss of vision in the centre of the eye, is caused by the build up of deposits on the retina at the back of the eye called ?drusen?. Many people have a version of Factor H that leads to a high risk of developing age-related macular degeneration. Even though we know Factor H is involved in the disease, we do not understand the reasons why. However, we have made much recent progress in understanding the functioning of Factor H. We discovered that Factor H has a tendency to clump together (or form self-aggregates) when present in large amounts, and this tendency is strongly augmented in the presence of the metal zinc. Zinc is known to inhibit Factor H regulation. Interestingly, very large amounts of zinc have been reported in the drusen of patients. While zinc-Factor H interactions may not be the only reason for drusen formation, the potential involvement of zinc in this process constitutes a very plausible idea for investigation. We wish to determine the molecular basis for the zinc-mediated aggregation (oligomer formation) of Factor H by making modified forms of Factor H and testing their effect on zinc binding. If successful, we will have unravelled the first one of the molecular mechanisms that lead to drusen formation, and this will open the way for the development of novel therapeutic strategies for the treatment of age-related macular degeneration.

我们的免疫系统对于保护我们免受所有类型的细菌，真菌和病毒感染至关重要。有不同类型的免疫防御在体内，和相关的这一建议被称为？先天免疫力？血液中的蛋白质叫什么互补？破坏入侵的外来细菌。虽然对细菌非常有效，但补体需要严格控制，使其不会攻击身体。自己的细胞。这种控制是通过一系列调节蛋白实现的，因子H就是这样一种蛋白。近年来，H因子与老年性黄斑变性有关，这是老年人失明的最常见原因。这种导致眼睛中心视力丧失的疾病是由眼睛后部视网膜上的沉积物引起的，称为？玻璃疣？许多人都有一个版本的因子H，导致发展年龄相关性黄斑变性的风险很高。尽管我们知道H因子与这种疾病有关，但我们不了解原因。然而，我们最近在理解因子H的功能方面取得了很大进展。我们发现，当大量存在时，因子H具有聚集在一起（或形成自聚集体）的趋势，并且这种趋势在金属锌的存在下强烈增强。已知锌抑制因子H调节。有趣的是，在患者的玻璃疣中已经报道了非常大量的锌。虽然锌-因子H相互作用可能不是玻璃疣形成的唯一原因，但锌在此过程中的潜在参与构成了一个非常合理的研究思路。我们希望通过制备修饰形式的H因子并测试其对锌结合的影响来确定H因子锌介导的聚集（寡聚体形成）的分子基础。如果成功，我们将揭开导致玻璃疣形成的第一个分子机制，这将为开发治疗年龄相关性黄斑变性的新治疗策略开辟道路。