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

我们的免疫系统对保护我们免受各种细菌、真菌和病毒感染至关重要。人体内有不同类型的免疫防御，与这个提议相关的叫做？先天免疫?血液中有哪些蛋白质叫做补体？消灭入侵的外来细菌。虽然对细菌非常有效，但补体需要严格控制，以免攻击身体。S自己的细胞。这种控制是通过一系列调节蛋白来实现的，因子H就是其中一种。近年来，因子H与年龄相关性黄斑变性有关，黄斑变性是老年人失明的最常见原因。这种疾病会导致眼睛中心的视力丧失，是由眼睛后部视网膜上被称为“黄斑”的沉积物堆积引起的。许多人都有一种导致老年性黄斑变性的高风险因子H。尽管我们知道因子H与这种疾病有关，但我们不知道其中的原因。然而，我们最近在了解H因子的功能方面取得了很大进展。我们发现，当H因子大量存在时，它有聚集在一起（或形成自聚集体）的倾向，并且这种倾向在金属锌的存在下被强烈增强。锌可以抑制因子H的调节。有趣的是，据报道病人的肾脏中含有大量的锌。虽然锌-因子H的相互作用可能不是形成脓疱的唯一原因，但锌在这一过程中的潜在参与构成了一个非常可信的研究想法。我们希望通过修饰因子H的形式并测试它们对锌结合的影响来确定因子H在锌介导下聚集（低聚物形成）的分子基础。如果成功，我们将揭开导致黄斑变性形成的第一个分子机制，这将为开发治疗老年性黄斑变性的新治疗策略开辟道路。

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.