The complement system plays a critical role in the host defense against microorganisms and in the modulation of inflammatory responses. Recently, it has been suggested that there may be a link between complement activation and vascular proliferation. Age-related macular degeneration (ARMD) is the leading cause of blindness in the Western world in individuals over 55 years of age. Although the nonexudative (dry) form of ARMD is more prevalent, catastrophic vision loss is more frequently associated with the exudative (wet) form, specifically from the complications of neovascularization of the choroid. The pathogenesis of new choroidal vessel formation (CNV) in exudative ARMD is poorly understood. Although inflammation has been implicated in the development of CNV the role of complement has not been explored. In the current proposal we wish to explore the role of complement in choroidal neovascularization using the mouse model of laser-induced CNV. Using this model, our recent results suggest that the complement system is central to the development of laser-induced choroidal angiogenesis. Thus, we propose to explore the role of complement and complement regulatory proteins in the development of experimental CNV, as well as the treatment effect of complement inhibition using soluble complement regulatory proteins.
The specific aims of this proposal are: 1. To study the complement system in the mouse model of laser-induced CNV. 2. To study complement regulatory proteins (CRPs) in the mouse model of laser-induced CNV. 3. To establish the complement (i.e. MAC) dependence and temporal expression of angiogenic growth factors in laser-induced CNV. We believe that these studies will lead to a better understanding of an important underlying molecular mechanism in the development of CNV (i.e. complement activation), and will help to identify new molecular targets for novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014623-03
Application #
6896378
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Dudley, Peter A
Project Start
2003-08-01
Project End
2006-01-04
Budget Start
2005-07-01
Budget End
2006-01-04
Support Year
3
Fiscal Year
2005
Total Cost
$117,740
Indirect Cost
Name
University of Louisville
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Davis, Stephen J; Lyzogubov, Valeriy V; Tytarenko, Ruslana G et al. (2012) The effect of nicotine on anti-vascular endothelial growth factor therapy in a mouse model of neovascular age-related macular degeneration. Retina 32:1171-80
Lyzogubov, Valeriy V; Tytarenko, Ruslana G; Bora, Nalini S et al. (2012) Inhibitory role of adiponectin peptide I on rat choroidal neovascularization. Biochim Biophys Acta 1823:1264-72
Liu, Juan; Jha, Purushottam; Lyzogubov, Valeriy V et al. (2011) Relationship between complement membrane attack complex, chemokine (C-C motif) ligand 2 (CCL2) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization. J Biol Chem 286:20991-1001
Manickam, Balasubramanian; Jha, Purushottam; Matta, Bharati et al. (2011) Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses. J Biol Chem 286:8472-80
Manickam, Balasubramanian; Jha, Purushottam; Hepburn, Natalie J et al. (2010) Suppression of complement activation by recombinant Crry inhibits experimental autoimmune anterior uveitis (EAAU). Mol Immunol 48:231-9
Matta, Bharati; Jha, Purushottam; Bora, Puran S et al. (2010) Antigen-specific tolerance inhibits autoimmune uveitis in pre-sensitized animals by deletion and CD4+CD25+ T-regulatory cells. Immunol Cell Biol 88:187-96
Bora, Nalini S; Jha, Purushottam; Lyzogubov, Valeriy V et al. (2010) Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice. J Biol Chem 285:33826-33
Lyzogubov, Valeriy V; Tytarenko, Ruslana G; Jha, Purushottam et al. (2010) Role of ocular complement factor H in a murine model of choroidal neovascularization. Am J Pathol 177:1870-80
Lyzogubov, Valeriy V; Tytarenko, Ruslana G; Thotakura, Sushma et al. (2009) Inhibition of new vessel growth in mouse model of laser-induced choroidal neovascularization by adiponectin peptide II. Cell Biol Int 33:765-71
Jha, Purushottam; Manickam, Balasubramanian; Matta, Bharati et al. (2009) Proteolytic cleavage of type I collagen generates an autoantigen in autoimmune uveitis. J Biol Chem 284:31401-11

Showing the most recent 10 out of 20 publications