The complement alternative activation pathway (AP) is a principal cause of tissue damage in human diseases and injury states. Therapeutic agents designed to inhibit harmful complement activity have begun to emerge in the clinical setting. The C3 convertases are the key 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 assembly and regulation is the key to therapeutic strategies for prevention of complement-related damage. Our long-range goal is to design new approaches for the prevention or inhibition of harmful complement. Of the three complement activation pathways, the alternative pathway (AP) in particular has been implicated in numerous disease and injury states. This proposal is directed to the AP and specifically to properdin, a component unique to the AP convertases and whose functions are not yet fully understood. Recently we, and others, have employed animal model systems to demonstrate that properdin is a promising therapeutic target for the amelioration of AP-dependent pathogenesis. In order to understand the mechanistic basis of properdin function and to develop a properdin-based strategy for the therapeutic inhibition of AP- dependent complement activity, we propose the following SPECIFIC AIMS:
Specific Aim 1. Use in vitro model systems to characterize the contribution of properdin pattern recognition activity to C activation.
Specific Aim 2. Elucidate the role(s) of properdin in animal models of AP-dependent pathogenesis.
Specific Aim 3. Develop anti-properdin reagents for the therapeutic inhibition of pathologic AP-dependent C activity. We expect the results from this work to have the potential to be highly translational and to significantly impact therapeutic strategies aimed at controlling the complement alternative pathway.

Public Health Relevance

The complement proteins protect us from infectious microorganisms but under other circumstances they can cause severe and potentially life-threatening tissue damage. The proposed research will provide new strategies and tools for successful therapeutic intervention in such cases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI051436-12
Application #
8707183
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Nasseri, M Faraz
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Kemper, Claudia; Hourcade, Dennis E (2008) Properdin: New roles in pattern recognition and target clearance. Mol Immunol 45:4048-56

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