Complement activation in glaucoma

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We have shown that one of the major genes with altered expression in the glaucomatous retina is complement component C1q. Retinal C1q is up-regulated early in the disease process in the DBA/2 mouse model of glaucoma. This finding has been recognized as very significant in the field of glaucoma as we have shown that a similar up-regulation occurs in laser induced monkey glaucoma as well as in human glaucoma. In addition we have made significant progress towards generating a congenic C1q knockout (KO) strain on the DBA/2 background which we will employ in future studies to understand the role of C1q in glaucoma. The changes in expression of C1q and other complement genes, suggest that a neuro-inflammatory process is operational in glaucomatous retinal ganglion cell (RGC) pathology. In fact we present preliminary evidence that an inflammatory reaction is critical for the development of RGC loss in the DBA/2 mouse. Based on the above and the role that complement plays in modulating adaptive immunity we propose the following hypothesis on how complement activation participates in the pathogenesis of glaucoma: Intermediate components of complement activation cause RGC axon and soma damage, either directly or indirectly (through effects on supportive cells, retinal glia, immune cells and extracellular matrix). To test this hypothesis we must first understand which of the many effector complement molecules is involved in this process. We thus propose the following specific aims: 1. Test the prediction that expression levels and/or amounts of intermediate complement components are altered in the retinas from induced and spontaneous (DBA/2) mouse models of glaucoma, as well as in laser induced primate glaucoma and human specimens from patients with glaucoma. 2. Characterize phenotypically the congenic DBA/2 C1q -/- animals we have generated in the previous funding period to determine whether complement activation through the classical pathway is involved in the pathophysiology of the disease. 3. Generate congenic DBA/2 C4 -/- and C3-/- animals and phenotype them in respect to RGC and axonal loss as well as glial activation to determine whether the C4 and C3 complement components are required for development of the glaucomatous pathology. 4. Determine whether C5 has a protective role in the pathogenesis of glaucoma by comparing the amount of RGC loss and glial activation in C5 KOs and wild type mice subjected to laser-induced IOP elevation. This proposal will dissect the various complement components to allow precise determination of the role of each one in the pathogenesis of glaucoma. Findings from this work will have wider implications for other neurodegenerative disease.