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.
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.
|Yan, Huimin; Zhou, Hui-Fang; Akk, Antonina et al. (2016) Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation. Arterioscler Thromb Vasc Biol 36:1660-9|
|Akk, Antonina; Springer, Luke E; Pham, Christine T N (2016) Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype. Front Immunol 7:325|
|Renner, Brandon; Tong, Hua Hua; Laskowski, Jennifer et al. (2016) Annexin A2 Enhances Complement Activation by Inhibiting Factor H. J Immunol 196:1355-65|
|Hourcade, Dennis E; Akk, Antonina M; Mitchell, Lynne M et al. (2016) Anti-complement activity of the Ixodes scapularis salivary protein Salp20. Mol Immunol 69:62-9|
|Bertram, Paula; Akk, Antonina M; Zhou, Hui-fang et al. (2015) Anti-mouse properdin TSR 5/6 monoclonal antibodies block complement alternative pathway-dependent pathogenesis. Monoclon Antib Immunodiagn Immunother 34:1-6|
|Java, Anuja; Liszewski, M Kathryn; Hourcade, Dennis E et al. (2015) Role of complement receptor 1 (CR1; CD35) on epithelial cells: A model for understanding complement-mediated damage in the kidney. Mol Immunol 67:584-95|
|Yan, Huimin; Zhou, Hui-Fang; Hu, Ying et al. (2015) Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation. J Rheum Dis Treat 1:5|
|Park, Hyon Ju; Guariento, Mara; Maciejewski, Mateusz et al. (2014) Using mutagenesis and structural biology to map the binding site for the Plasmodium falciparum merozoite protein PfRh4 on the human immune adherence receptor. J Biol Chem 289:450-63|
|Pham, Christine T N; Thomas, Dennis G; Beiser, Julia et al. (2014) Application of a hemolysis assay for analysis of complement activation by perfluorocarbon nanoparticles. Nanomedicine 10:651-60|
|Zhou, Hui-fang; Yan, Huimin; Bertram, Paula et al. (2013) Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation. Proc Natl Acad Sci U S A 110:E4335-44|
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