Our research goal is to understand the biological role of the terminal complement complex, C5b-9. The complement system is activated and the C5b-9 complexes are assembled in the central nervous system in inflammatory, immune mediated, and degenerative disorders, such as multiple sclerosis, Alzheimer's disease, and ischemic vascular injury. Others and we have shown that eukaryotic cells, including oligodendrocytes (OLG) are protected from the cytolytic C5b-9 by inhibitory proteins CD55 and CD59, and by elimination of membrane-inserted C5b-9. Cells exposed to sublytic C5b-9 therefore survive. OLG that survive show the OLG progenitor-like phenotype: expression of protooncogenes and loss of mRNA encoding myelin proteins. C5b-9 induces DNA synthesis and enhances OLG survival. These findings led us to examine new genes activated in OLG by C5b-9 that may be involved in cell cycle. We have cloned a novel gene RGC-32 (Response Gene to complement), which is activated by C5b-9 and involved in cell cycle. Overexpression of RGC-32 in OLG by transfection increased DNA synthesis. C5b-9 also enhances OLG survival by protecting OLG from apoptotic death. We suggest that the C5b-9-induced cell cycle entry and survival represent beneficial response to inflammation, critical for OLG recovery and remyelination. The mechanisms by which C5b-9 regulates OLG survival and the role of C5b-9 in remyelination will be investigated.
In Aim 1, we will determine; (i) the C5b-9-mediated regulation of pro- and anti- about apoptotic BAD and BCL-2/BCL-XL molecules in OLG apoptosis, and (ii) the membrane signaling responsible for C5b-9 rescue of OLG from apoptosis.
In Aim 2, we will test whether RGC-32 prolongs OLG survival through cdc2-mediated phosphorylation of BCL-2/BCL-XL.
In Aim 3, we will examine whether C5b-9 has a beneficial role by rescuing OLG from apoptotic death in vivo. By inducing experimental allergic encephalitis in C5-deficient and control mice, and in C6-deficient rats, the potential of C5b-9 to enhance OLG survival and remyelination will be evaluated. Our application is novel in that it integrates the newly identified function of sublytic C5b-9 to promote OLG survival with the recently discovered role of RGC-32 in enhancing cdc2-dependent phosphorylation of BCL-2, to define a novel regulatory mechanism controlling OLG survival. Our proposed studies will provide an unique model system to elucidate the biology of sublethally injured OLG and may lead to the identification of regulatory factors that can enhance OLG survival and remyelination.
| Vlaicu, Sonia I; Tegla, Cosmin A; Cudrici, Cornelia D et al. (2013) Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer. Immunol Res 56:109-21 |
| Tegla, Cosmin A; Cudrici, Cornelia; Patel, Snehal et al. (2011) Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res 51:45-60 |
| Tegla, Cosmin A; Cudrici, Cornelia; Rozycka, Monika et al. (2011) C5b-9-activated, K(v)1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation. Exp Mol Pathol 91:335-45 |
| Vlaicu, Sonia I; Tegla, Cosmin A; Cudrici, Cornelia D et al. (2010) Epigenetic modifications induced by RGC-32 in colon cancer. Exp Mol Pathol 88:67-76 |
| DeBoy, Cynthia A; Rus, Horea; Tegla, Cosmin et al. (2010) FLT-3 expression and function on microglia in multiple sclerosis. Exp Mol Pathol 89:109-16 |
| Fosbrink, Matthew; Cudrici, Cornelia; Tegla, Cosmin A et al. (2009) Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells. Exp Mol Pathol 86:87-94 |
| Tegla, Cosmin A; Cudrici, Cornelia; Rus, Violeta et al. (2009) Neuroprotective effects of the complement terminal pathway during demyelination: implications for oligodendrocyte survival. J Neuroimmunol 213:3-11 |
| Cudrici, Cornelia; Ito, Takahiro; Zafranskaia, Ekaterina et al. (2008) Complement C5 regulates the expression of insulin-like growth factor binding proteins in chronic experimental allergic encephalomyelitis. J Neuroimmunol 203:94-103 |
| Oh, Sangjin; Cudrici, Cornelia; Ito, Takahiro et al. (2008) B-cells and humoral immunity in multiple sclerosis. Implications for therapy. Immunol Res 40:224-34 |
| Vlaicu, Sonia I; Cudrici, Cornelia; Ito, Takahiro et al. (2008) Role of response gene to complement 32 in diseases. Arch Immunol Ther Exp (Warsz) 56:115-22 |
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