Complement Convertase: Assembly, Function and Regulation

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Complement marks infectious agents for immune clearance or lysis, promotes the local inflammatory response, and facilitates B cell activation and Ab production. Complement is also active during apoptosis, reproduction, and tissue regeneration although the biological significance of its roles in these cases is unclear. On the negative side, complement is a principal cause of tissue damage in human diseases. While there are several first-generation complement inhibitors undergoing clinical trials, there remains a compelling need for novel complement-based reagents for clinical use. The C3 convertases are the primary enzymes of complement activation. Complement-related disease and injury can be traced both to inappropriate convertase assembly (e.g. autoimmunity), and to convertase regulator dysfunction (e.g. atypical HUS, age-related macular degeneration). The control of convertase activation and regulation is the key to therapeutic strategies for both the prevention of complement-related damage, and the promotion of complement activity towards pathogens, tumors, and other appropriate targets. Our long-range goals are to design new clinical approaches based on an understanding gained from studies of the C3 convertases. We have discovered that properdin binds directly to certain microbial surfaces where it initiates convertase assembly and complement activation. These findings specifically account for the critical role of properdin in the host defense against Neisseria infection, suggest that properdin likely plays a major role in the identification of other microbial targets, and support a model of complement activation in which properdin plays a much more prominent role than reflected in current thinking. We have also obtained evidence that properdin-directed complement activation plays a role in the programmed removal of undesirable cells (apoptosis). We believe that an intense examination of properdin-directed complement activation will lead to a new understanding of the mechanism and scope of complement activation in immunity and in cell and tissue-level housekeeping functions, and will result in novel therapeutic targets and strategies for the suppression and the guidance of complement-dependent destruction. To that end we propose experiments directed to the following specific aims: 1. Elucidate the kinetics and mechanism of properdin-directed complement activation. 2. Characterize the impact of "properdin-tagging" on nucleated cells and pathogens. 3. Define the structural elements that determine properdin in target recognition.