The role and diagnosis of complement dysregulation in disease

这项拟议中的研究解决了免疫系统的核心部分是如何控制的基本问题。这是相关的，因为了解这些机制及其在疾病中的干扰将更好地帮助我们识别那些有疾病风险的人，以针对性地预防和治疗。补体是我们抵抗感染的免疫防御的一部分，是血浆中的一组蛋白质，可以识别，攻击和摧毁细菌。补体的这种作用对健康很重要，有补体缺陷的人容易受到感染。然而，这种防御是有代价的。由于其强大的细胞杀伤特性，必须严格控制补体，以防止损害我们自己的细胞导致疾病。最近，很明显，补体蛋白的小遗传变化，当存在于特定组合中时，会影响这种控制，并大大增加补体攻击我们自己的细胞和损害器官的风险，特别是肾脏和眼睛。其中包括儿童常见的不可逆性肾衰竭（阿胡斯）和老年人最常见的致盲原因（AMD）。我们计划研究补体中这些小的遗传变化（常见的称为多态性，或罕见的称为突变）导致失控的方式。要做到这一点，我们将首先了解补体是如何被激活和控制的，使用工具来研究蛋白质相互作用的方式。我们将使用这些工具来测试多态性和突变如何削弱控制。这些知识将以两种方式用于有益于健康。首先，我们将开发简单而廉价的血液测试来识别携带危险多态性的人;然后可以密切监测那些处于危险中的人，以降低患病的风险。第二，更好地了解控制中的问题将使设计适当的治疗方法，以恢复对补体系统的控制，从而预防和治疗疾病。这项工作将由一个在补体生物学和遗传学方面具有公认专业知识的团队进行，该团队已经为了解补体如何驱动疾病做出了贡献。这项工作涉及分析蛋白质，无论是从患者或健康志愿者那里获得的，还是在实验室中制造的，以发现这些蛋白质的微小变化如何易患AMD等常见疾病和阿胡斯等致命疾病。

The proposed research addresses basic questions of how a central part of the immune system is controlled. It is relevant because understanding of these mechanisms and their disturbance in disease will better equip us to identify those at risk of disease to target prevention and treatment.Complement is part of our immune defence against infection, a group of proteins in blood plasma that recognise, attack and destroy bacteria. This role of complement is important for health and people with complement defects are susceptible to infections. However, this defence comes at a price. Because of its powerful cell-killing properties, complement must be tightly controlled to prevent damage to our own cells resulting in disease. Recently, it has become apparent that small inherited changes in complement proteins, when present in specific combinations, affect this control and greatly increase the risk that complement will attack our own cells and damage organs, particularly kidney and eye. These include a common form of irreversible kidney failure in children (aHUS) and the commonest cause of blindness in the elderly (AMD). We plan to study the ways in which these small inherited changes (either common and called polymorphisms or rare and called mutations) in complement lead to loss of control. To do this we will first gain an understanding of how complement is normally activated and controlled using tools to study the ways that proteins interact. We will use these tools to test how the polymorphisms and mutations weaken control. This knowledge will be used to benefit health in two ways. First, we will develop simple and inexpensive blood tests to identify people carrying risky polymorphisms; those at risk can then be monitored closely to reduce the risk of getting disease. Second, better understanding of the problems in control will enable the design of appropriate treatments to restore control in the complement system to prevent and treat disease.The work will be performed by a team with proven expertise in complement biology and genetics that has already made contributions to understanding how complement drives disease. The work involves analyses of proteins, either obtained from patients or healthy volunteers or manufactured in the laboratory, to discover how small changes in these proteins predispose to common diseases such as AMD and lethal disorders such as aHUS.