Molecular recognition and regulation of the lectin pathway of complement activation

补体系统是哺乳动物免疫系统的基本组成部分，可以中和潜在的有害细菌、病毒和寄生虫。该系统的一个相对不为人所知的分支，称为凝集素途径，依赖于对入侵微生物表面的碳水化合物的识别来启动补体级联。凝集素途径在感染的早期阶段尤其重要，在宿主能够合成特异性抗体之前，或者当免疫系统受到抑制时，例如在HIV感染期间或化疗后。它直接杀死病原体，并刺激和指导免疫系统的其他部分产生适当的反应。虽然凝集素途径通常具有保护作用，但在某些条件下，它会对宿主组织造成严重的损伤。例如，凝集素途径依赖的补体激活被认为会导致心肌梗死后血流恢复后的实质性心血管损伤。在这项拨款申请中，我们的目标是通过研究这些成分相互作用以启动和调节反应级联的方式，更好地了解补体活化的凝集素途径。我们已经建立了利用重组DNA技术生产关键元素的方法，因此可以系统地研究它们的作用方式。利用这些研究的结果，我们计划开发凝集素途径激活的特异性抑制剂。这些抑制剂将是帮助我们了解凝集素途径在复杂生物过程中的作用的有用工具，也将作为治疗疾病的潜在药物，包括心脏和肾脏疾病。该项目的另一个目标是改变凝集素途径成分的性质，使它们与存在于肿瘤细胞表面但通常在健康组织中找不到的碳水化合物结合。我们将测试这些修饰过的成分刺激免疫系统来中和肿瘤细胞的能力。我们的研究提供的知识将通过在高质量的科学期刊上发表和在国际会议上发表来转化为科学界。我们的研究将通过大学新闻处的大学和部门网页向公众公布。特别重要的发现将刊登在双月刊的《大学通讯》和《大学年报》中，以突出大学的主要成就。

The complement system is a fundamental part of the mammalian immune system, neutralising potentially harmful bacteria, viruses and parasites. A relatively poorly understood branch of this system, called the lectin pathway, relies on recognition of carbohydrates on the surfaces of invading microorganisms to initiate the complement cascade. The lectin pathway is particularly important in the early stages of infection, before specific antibodies can be synthesized by the host or when the immune system is suppressed, for example during HIV infection or following chemotherapy. It kills pathogens directly and also stimulates and directs other parts of the immune system to generate an appropriate response. Although the lectin pathway normally has a protective role, under certain conditions, it can cause severe damage to host tissues. For example, lectin pathway dependent complement activation is believed to cause substantial cardiovascular damage following restoration of blood flow following myocardial infarction. In this grant proposal, we aim to develop a better understanding of the lectin pathway of complement activation by studying the way in which the components interact with each other to initiate and regulate the reaction cascade. We have already established methods for producing key elements using recombinant DNA technology, so that their mode of action can be investigated in a systematic way. Using the results from these studies, we plan to develop specific inhibitors to lectin pathway activation. These inhibitors will be useful tools to help us understand the role of the lectin pathway in complex biological processes and will also serve as potential drugs for the treatment of diseases, including heart and kidney disease. An additional goal of this project is to change the properties of components of the lectin pathway so that they bind to carbohydrates that are present on the surfaces of tumour cells but are not normally found on healthy tissues. We will test the abilities of these modified components to stimulate the immune system to neutralize tumour cells. The knowledge provided by our research will be translated to the scientific community through publication in high quality scientific journals and by presentations at international conferences. Our research will be communicated to the general public through the University and Departmental Web pages via the University Press Office. In particular, important discoveries will be published in the bimonthly University newletter and in the Annual Report, which highlights major achievements of the University.